Application of Quinoline Ring in Structural Modification of Natural Products

Zhao, Yu-Qing; Li, Xiaoting; Guo, Hong-Yan; Shen, Qing-Kun; Quan, Zhe-Shan; Luan, Tian

doi:10.3390/molecules28186478

Open AccessReview

Application of Quinoline Ring in Structural Modification of Natural Products

by

Yu-Qing Zhao

^1,†,

Xiaoting Li

^1,†,

Hong-Yan Guo

¹,

Qing-Kun Shen

¹,

Zhe-Shan Quan

^1,* and

Tian Luan

^2,*

¹

Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China

²

Department of Pharmacy, Shenyang Medical College, Shenyang 110034, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Molecules 2023, 28(18), 6478; https://doi.org/10.3390/molecules28186478

Submission received: 11 August 2023 / Revised: 4 September 2023 / Accepted: 5 September 2023 / Published: 6 September 2023

(This article belongs to the Section Medicinal Chemistry)

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Abstract

:

Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological processes in heterocycles. Many pharmacological compounds, including saquinavir and chloroquine, have been marketed as quinoline molecules with good anti-viral and anti-parasitic properties. Therefore, in this review, we summarize the medicinal chemistry of quinoline-modified natural product quinoline derivatives that were developed by several research teams in the past 10 years and find that these compounds have inhibitory effects on bacteria, viruses, parasites, inflammation, cancer, Alzheimer’s disease, and others.

Keywords:

natural products; quinoline; pharmacological activities

1. Introduction

Active molecules of natural products have always been an important source of drug leads due to their diverse chemical structures and extensive pharmacological activities. According to statistics, from January 1981 to September 2019, the FDA has approved 1881 new drugs, of which about half are directly or indirectly derived from natural compounds [1]. Quinoline, also known as benzo[b]pyridine, is a nitrogen-containing heterocyclic aromatic molecule with a weak tertiary base that can form salts with acids and perform electrophilic substitution reactions and reactions resembling those of pyridine and benzene. Quinolines have numerous biological effects, such as antibacterial [2,3,4], antifungal [5], antituberculosis [6], antiprotozoal [7,8], antineoplastic [9], anti-viral [10], anti-cholesterol medications [11], analgesics [12], anti-disease Alzheimer’s pharmaceuticals [13], and more.

In fact, quinoline drugs are widely used in the pharmaceutical industry. Many drugs contain quinoline rings. For example, quinine (Figure 1) is one of the natural products is present in the bark of cinchona, which has been used to treat malaria. Camptothecin (Figure 1) is a quinoline alkaloid extracted from Camptotheca acuminata, and its analogue, topotecan (Figure 1), are effective antitumor drugs. And other chemical drugs, such as dibucaine (Figure 1) as a local anesthetic, montelukast (Figure 1) for asthma, aripiprazole (Figure 1) as an antipsychotic, vesnarinonez (Figure 1) as a cardiac agent, etc., all contain quinoline structure. Creating novel homologs with enhanced biological activity and fewer potentially harmful side effects has been a goal for many years. Emphasizing the biological activities of the quinolones, we will highlight some recent results regarding the development of novel quinoline-natural product hybrids in this study.

Figure 1. The chemical structures of introduction.

2. Method

Published articles, network databases (PubMed, Science Direct, SCI Finder, CNKI), and clinical trial websites https://clinicaltrials.gov/ (accessed on 31 September 2022) related to natural products and quinoline derivatives) were included in the discussion. The 94 studies that met the inclusion criteria were chosen for discussion. It is possible to categorize natural quinoline derivative compounds according to their biological activity by screening. The entire text is divided into sections based on how biologically active their derivatives are, namely, in the following categories: inhibition of bacteria, viruses, parasites, inflammation, cancer, Alzheimer’s disease, etc. The biological activities of quinoline derivatives were discussed in detail. It is worth noting that most derivatives exhibit enhanced biological activity and reduced cytotoxicity compared to lead compounds. Quinoline has many advantages and can be widely used in the synthesis of natural product derivatives to enhance the properties of drug bulks.

3. Pharmacological Activities

3.1. Anti-Alzheimer’s Disease Activity

Coumarin (chemical formula (CF): C₉H₆O₂, molecular weight (MW): 146.14, 2H-1-benzopyran-2-one) is a phenolic compound widely found in orchids, legumes, Umbelliferae, Compositae, Rutaceae, and other plants. Duarte and colleagues [14] synthesized quinoline-substituted compounds 1–4 (Figure 2) (Table 1) at the seventh position of coumarin and determined their AChE/BChE activity regulation. Compound 2a, containing a strong electron-donating group (methoxy) at position 7, were against both enzymes (AChE IC₅₀ = 194 μM and BChE IC₅₀ = 255 μM), being the only representative dual compound of the entire series. However, compound 2b, which has the same substitution pattern at position 7 and a different aminoquinoline at position 3, showed selective activity against the AChE enzyme (AChE IC₅₀ = 181 μM, selectivity ratio > 2.75). Compound 3, with the same amidoquinoline as compound 2b at position 3 and an electron-withdrawing atom (chloride atom) at position 7 of the coumarin scaffold, was the only selective BChE inhibitor of the entire series (BChE IC₅₀ = 146 μM, selectivity ratio < 0.29). The most active and selective AChE compound among all others was compound 4, which had an electron-donating group (diethylamine) at position 7 and a 6-quinoline derivative at position 3 (AChE IC₅₀ = 159 μM, selectivity ratio > 3.13). This result was intriguing because other electron-donating groups such as methyl and methoxy groups, compounds 1 and 2c, respectively, present at position 7, showed results that were the opposite of this trend, suggesting that the diethylamine substituents at position 7 are only marginally important for the AChE binding affinity. Compound 4 is also an iron chelator (100 μM Fe chelation = 72.87%), forming a well-defined stacking contact with Phe330 and interacting with Tyr121 residues via hydrogen bonding.

Wang and colleagues [15] designed and synthesized 2-arylethenylquinoline derivatives 5 and 6 (Figure 1) (Table 1) against AChE and BChE. The results showed that compounds 5 and 6 had moderate ChE inhibitory activity (IC₅₀ of compound 5 AChE and BChE were 64.0 ± 0.1 and 0.2 ± 0.1 μM, respectively; and the IC₅₀ of compound 6 AChE and BChE were 68.3 ± 0.1 and 1.0 ± 0.1 μM, respectively). These two compounds showed high selectivity for BChE; however, their inhibitory activity against ChE was significantly weaker than that of positive control tacrine. Even the most energetic compound 5 was 640- and 7-fold weaker than tacrine against AChE and BChE, respectively.

Galantamine (CF: C₁₇H₂₂ClNO₃, MW:323.8145, (4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) was initially isolated and extracted from the bulbs of snowdrops. However, due to the scarcity of the extraction species and the high cost of the extraction, numerous businesses throughout the world started producing galantamine by chemical synthesis. Ţînţaş and colleagues [16] synthesized dihydroquinoline galanthamine derivatives 7a–b (Figure 2) (Table 1) and evaluated their in vitro inhibitory activity on AChE in the human body. Compound 7a could not be assessed since it was insoluble in water; however, compound 7b had an IC₅₀ larger than 10 μM. Additionally, its activity was significantly lower than that of the parent galanthamine.

Caffeic acid (CA, CF: C₉H₈O₄, MW: 180.15, 3-(3,4-dihydroxyphenyl)- (9CI, ACI)) is derived from the whole plant of Solidago virga-urea L.var.leiocarpa, the fruit of Crataegus pinnatifida Bge., and others. Benchekroun and colleagues [17] synthesized a caffeic acid derivative 8 (Figure 2) (Table 1) and tested its antioxidant capacity. The experimental findings showed compound 8 showed 25% or more significant neuroprotection against H₂O₂ damage at 10 μM.

Chromones (CF: C₉H₆O₂, MW: 146.1427, 2,3-Benzo-4-pyrone), scientific name benzo-γ-pyrone, are widely present in plants, and some are colored substances, so their matrixes are called chromone. Shah and colleagues [18] synthesized chromone quinoline derivatives 9a–e and 10a–e (Figure 2) (Table 1) and evaluated their cholinesterase inhibitory activity. The screening of quinolinyl-chromone derivatives 9a–e and 10a–e for ChE revealed that most are selective BChE inhibitors. The active group connected to the quinoline acyl chalcone derivative has significant AChE inhibitory activity. The most effective molecule against BChE among 2,6-dimethyl quinoline derivatives is 9e (2,3-dihydrobenzo[b]1,4-dioxin-6-yl as Ar substituent) with an IC₅₀ of 0.56 ± 0.02 μM. The exceptional inhibitory potential of compound 9e may be attributed to the presence of highly electronegative oxygen atoms (1,4-dioxane) and a tiny functional group (-CH₃). The chemical 10e likewise contains 1,4-dioxane, but it has a methoxy (-OCH₃) functional group in its basic structure, which may limit its inhibitory effectiveness against BChE. Compounds 10a and 10b inhibit BChE significantly, with IC₅₀ of 0.94 ± 0.04 μM and 0.73 ± 0.03 μM, respectively. These compounds have 5-methylfuran-2-yl (for 10a) and 2,5-dimethylfuran-3-yl (for 10b) substitutions at the -Ar position of the quinolinyl ring. When the experimental data from both series were examined, a modest decrease in the inhibitory potential was observed in the presence of a 6-methoxy group at the quinolinyl moiety. To investigate the putative mechanism of ChEs inhibition, detailed kinetic investigations of the most effective derivatives were conducted. The results indicated that compound 9e could interact with both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE.

Figure 2. The chemical structures of anti-Alzheimer’s disease compounds 1–10.

Table 1. Quinoline derivatives with anti-Alzheimer’s disease activity.

Compd.	Activity	Target	Origin	Ref
1	AChE IC₅₀ = 324.88 μM	AChE	synthetic	[14]
2a	AChE IC₅₀ = 194 μM BChE IC₅₀ = 255 μM	ACHE BCHE	synthetic	[14]
2b	AChE IC₅₀ = 181.72 μM, selectivity ratio > 2.75	ACHE	synthetic	[14]
2c	AChE IC₅₀ > 500 μM BChE IC₅₀ > 500 μM	-	synthetic	[14]
2d	AChE IC₅₀ > 500 μM BChE IC₅₀ > 500 μM	-	synthetic	[14]
3	BChE IC₅₀ = 146.74 μM, selectivity ratio < 0.29	BCHE	synthetic	[14]
4	AChE IC₅₀ = 159.53 μM, selectivity ratio > 3.13	ACHE	synthetic	[14]
5	AChE IC₅₀ = 64.0 μM BChE IC₅₀ = 0.2 μM	ACHE BCHE	synthetic	[15]
6	AChE IC₅₀ = 68.3 μM BChE IC₅₀ = 1.0 μM	ACHE BCHE	synthetic	[15]
7a	-	-	synthetic	[16]
7b	AChE IC₅₀ > 10 μM	ACHE	synthetic	[16]
8	25% H₂O₂ damage at 10 μM.	-	synthetic	[17]
9a	AChE IC₅₀ = 2.99 μM BChE IC₅₀ = 0.91 μM	ACHE BCHE	synthetic	[18]
9b	AChE IC₅₀ = 0.32 μM BChE IC₅₀ = 0.90 μM	ACHE BCHE	synthetic	[18]
9c	AChE IC₅₀ = 3.99 μM BChE IC₅₀ = 0.64 μM	ACHE BCHE	synthetic	[18]
9d	AChE IC₅₀ = 3.45 μM BChE IC₅₀ = 0.63 μM	ACHE BCHE	synthetic	[18]
9e	AChE IC₅₀ = 44.46 μM BChE IC₅₀ = 0.56 μM	ACHE BCHE	synthetic	[18]
10a	AChE IC₅₀ = 43.36 μM BChE IC₅₀ = 0.94 μM	ACHE BCHE	synthetic	[18]
10b	AChE IC₅₀ = 46.42 μM BChE IC₅₀ = 0.73 μM	ACHE BCHE	synthetic	[18]
10c	AChE IC₅₀ = 3.91 μM BChE IC₅₀ = 2.15 μM	ACHE BCHE	synthetic	[18]
10d	AChE IC₅₀ = 3.36 μM BChE IC₅₀ = 2.36 μM	ACHE BCHE	synthetic	[18]
10e	AChE IC₅₀ = 40.29 μM BChE IC₅₀ = 1.32 μM	ACHE BCHE	synthetic	[18]

Summary: Coumarin, 2-aryl, and Chromones-linked quinoline derivatives can enhance their AChE/BChE activity. Among them, compounds 9b and 9e showed inhibitory effects on AchE and BchE, with IC₅₀ values of 0.32 and 0.56 μM, respectively. When the 6 position of Chromones is methyl, the activity is significantly higher than that of methoxy; the activity is most obvious when the R group is furan. In addition, coumarin–quinoline derivatives 3 and 4 showed inhibitory effects on AchE and BchE, with IC₅₀ values of 146.74 and 153.53 μM, respectively; therefore, the Chromones-linked quinoline derivatives have the value of further research.

3.2. Anti-Osteoporosis Activity

Oleanolic acid (OA, CF: C₃₀H₄₈O₃, MW: 456.70, (3β)-3-Hydroxyolean-12-en-28-oic acid) is a kind of pentacyclic triterpenoid obtained by separating and extracting from the fruit of the whole herb of the gentian family, the genus of the genus Radix, or Ligustrum lucidum. It exists in free form and glycoside in polyphenols in plants. Li and colleagues [19] tested the inhibitory activity of OA derivatives 11 (Figure 3) (Table 2) in the formation of TRAP-positive, osteoclast-like multinucleated cells (OCLs) induced by the effect of 1a, 25-dihydroxy vitamin D₃ [1a,25(OH)₂D₃] effect. The results showed that compound 11 exhibited good activity at 20 μM (OCL% = 73.0%), which was better than OA at 20 μM. Encouragingly, compound 11 showed moderate activity even at 2 μM (OCL% = 18.9%).

Pregnenolone (CF: C₂₁H₃₂O₂, MW: 316.48, 3β-Hydroxy-5-pregnen-20-one), a naturally occurring endogenous steroid, is well-known as one of the biosynthetic precursors of steroid hormones. Maurya and colleagues [20] synthesized pregnenolone derivatives 12a–b (Figure 3) (Table 2) and tested its osteogenic effect. Compared with untreated control cells, compounds 12a and 12b significantly increased ALP activity. Among the compounds studied, compound 12a showed the greatest osteogenic effect according to the ALP activity evaluation. At the concentration of 1 pM and 100 pM the ALP activity increased by 100% and 85%, respectively. In addition, studies have shown that compound 12a can significantly increase the formation of mineral nodules, and compound 12a upregulates the expression of osteogenic markers BMP-2, RUNX-2, and OCN.

Figure 3. The chemical structures of anti-osteoporosis compounds 11–12.

Table 2. Quinoline derivatives with anti-osteoporosis activity.

Compd.	Activity	Target	Origin	Ref
11	2 μM OCL% = 18.9% 20 μM OCL% = 73.0%	-	synthetic	[19]
12a	1 pM ALP% = 100% 100 pM ALP% = 85%	ALP, BMP-2, RUNX-2, OCN	synthetic	[20]
12b	1 pM ALP% = 70% 100 pM ALP% = 60%	ALP	synthetic	[20]

Summary: The introduction of quinoline by oleanolic acid only showed moderate activity. The introduction of quinoline by pregnenolone still showed strong ALP activity at a concentration of 1 pM, and there was some research on its mechanism. The anti-osteoporosis activity of compound 12a has a certain research value.

3.3. Anti-Viral Activity

Andrographolide (CF: C₂₀H₃₀O₅, MW: 350.45, 3-[2-[Decahydro-6-hydroyx-5-(hydroxymethyl)-5,8a-dimethyl-2-methylene-1-naphthalenylethylidene]dihydro-4-hydroxy-2(3H)-furanone), is derived from the leaves of Andrographis paniculata. Li and colleagues [21] synthesized andrographolide quinoline derivative 13–14 (Figure 4) (Table 3) and tested their anti-Zika virus activity. The results show that the EC₅₀ of compound 13 is 1.3 μM. SI > 16 (CC₅₀ values of SNB-19 and Vero cell lines are 22.7 and 20.9 μM). EC₅₀ of compound 14 is 4.5 μM. SI > 19 (CC₅₀s of SNB-19 and Vero cell lines are 88.7 and 85.0 μM). In conclusion, compounds 13 and 14 have good anti-ZIKV virus activity.

Baltina and colleagues [22] tested the anti-ZIKV virus activity of glycyrrhizic acid derivatives 15a–b (Figure 4) (Table 3) and found that these two compounds 15a–b did not have good anti-Zika virus activity, the IC₅₀ value of compound 15a is less than 30 μM.

Wang and colleagues [23] tested the glycyrrhetinic acid quinoline derivative 16 (Figure 4) (Table 3) and tested its anti-HBV activity. Compound 16 inhibits HBV DNA replication with IC₅₀ of 15.30 μM (SI > 111.0), showing strong anti-HBV activity.

Figure 4. The chemical structures of anti-viral compounds 13–16.

Table 3. Quinoline derivatives with anti-viral activity.

Compd.	Activity	Target	Origin	Ref
13	anti-Zika virus EC₅₀ = 1.3 μM	-	synthetic	[21]
14	anti-Zika virus EC₅₀ = 4.5 μM	-	synthetic	[21]
15a	anti-Zika virus IC₅₀ < 30 μM	ZIKV NS2B-NS3 protease	synthetic	[22]
15b	anti-Zika virus IC₅₀ < 30 μM	ZIKV NS2B-NS3 protease	synthetic	[22]
16	anti-HBV IC₅₀ = 15.30 μM	-	synthetic	[23]

3.4. Anti-Hyperglycemic Activity

Lupeol (CF: C₃₀H₅₀O, MW: 426.7174, (3β)-Lup-20(29)-en-3-ol) is a compound found in the epidermis of lupin seeds, fig latex, and rubber. Reddy and colleagues [24] synthesized lupeol quinoline derivative 17 (Figure 5) (Table 4) and measured its anti-lipid activity. The hypolipidemic activity of derivative 17 was screened in mice at a dose of 50 mg/kg body weight. Blood cholesterol decreased by 27% (p < 0.05). Compound 17 showed good cholesterol-lowering effectiveness. Unfortunately, compound 17 reduces HDL-C.

Figure 5. The chemical structures of anti-hyperglycemic compound 17.

Table 4. Quinoline derivatives with anti-hyperglycemic activity.

Compd.	Activity	Target	Origin	Ref
17	Blood cholesterol decreased 27%	triglycerides	synthetic	[24]

3.5. Anti-Inflammatory Activity

Nam and colleagues [25] synthesized a series of resveratrol derivatives 18–22 (Figure 6) (Table 5) and measured their anti-inflammatory activities. The iEI value of compounds 18–22 is higher than that of the parent compound (iEI values of compounds 18–22 are 3.75, 3.18, 4.84, 2.11, and 4.27, respectively).

Glycyrrhetinic acid (GA, CF: C₃₀H₄₆O₄, MW: 470.69, 3β-hydroxy-11-oxo-18βH-Olean-12-en-30-oic acid) is a well-known pentacyclic triterpene extracted from liquorice root. Bian and colleagues [26] synthesized quinoline glycyrrhetinic acid derivative 23 (Figure 6) (Table 5) and measured its cytotoxicity and anti-inflammatory activities. Because of its low cytotoxicity, compound 23 was chosen for further investigation of anti-inflammatory effects. The inhibitory effect of quinoline compound 23 in glycyrrhetinic acid structure on IL-6 was significantly stronger than that of glycyrrhetinic acid.

Bakuchiol (CF: C₁₈H₂₄O, MW: 256.383, 4-(3,7-Dimethyl-3-vinylocta-1,6-dien-1-yl)phenol) is a natural plant component found in plant seeds. Ma and colleagues [27] synthesized quinoline bakuchiol derivatives 24–25 (Figure 6) (Table 5) and evaluated their anti-inflammatory activity in vitro. Adding quinoline structure did not increase BAK activity but considerably lowered its toxicity. Compound 24 had a moderate inhibitory effect on NO, but compound 25 had a strong inhibitory effect. Compounds 24–25 slightly inhibited IL-6 (p < 0.05 vs. LPS group) but did not affect TNF-a.

Figure 6. The chemical structures of anti-inflammatory compounds 18–25.

Table 5. Quinoline derivatives with anti-inflammatory activity.

Compd.	Activity	Target	Origin	Ref
18	iEI = 3.75	IL-1β, IL-6	synthetic	[25]
19	iEI = 3.18	IL-1β, IL-6	synthetic	[25]
20	iEI = 4.84	IL-1β, IL-6	synthetic	[25]
21	iEI = 2.11	IL-1β, IL-6	synthetic	[25]
22	iEI = 4.27	IL-1β, IL-6	synthetic	[25]
23	IL-6 stronger than that of glycyrrhetinic acid.	IL-6, TNF-α, NO, iNOS, COX-2	synthetic	[26]
24	moderate inhibitory effect on NO	Erythroid 2-related factor 2, Heme oxygenase-1	synthetic	[27]
25	strong inhibitory effect on NO	Erythroid 2-related factor 2, Heme oxygenase-1	synthetic	[27]

3.6. Antithrombotic Activity

Isosteviol (CF: C₂₀H₃₀O₃, MW: 318.4504, (4α,8β,13β)-13-Methyl-16-oxo-17-norkauran-18-oic acid) has the structural characteristics of tetracyclic diterpenoids. Chen and colleagues [28] synthesized an isosteviol–quinoline derivative 26 (Figure 7) (Table 6) and evaluated it in vitro FXa inhibition. The modification impact may not be optimum due to the Ki value of 26 on FXa being 4.177 μM, which is lower than the positive control for antithrombotic activity (K_i = 3.4 nM).

Figure 7. The chemical structures of antithrombotic compound 26.

Table 6. Quinoline derivatives with antithrombotic activity.

Compd.	Activity	Target	Origin	Ref
26	antithrombotic Ki = 3.4 nM	FXa	synthetic	[28]

3.7. Anti-Parasitic Activity

Cinchonasine (CF: C₂₀H₂₄N₂O₂, MW: 324.417, (8S,9R)-6′-Methoxy-cinchona-9-ol sulfate dihydrate) is the main alkaloid in the bark of the cinchona tree and its congeners. The structure of cinchonasine includes a quinoline ring. Leverrier and his colleagues [29] evaluated the anti-parasitic activity of cinchona–alkaloid derivatives 27a–c (Figure 8) (Table 7). According to the results, compounds 27a–c had good anti-T. brucei activity (IC₅₀s of compound 27a–c are 0.37, 0.39, and 0.40 μg/mL, respectively), and good resistance to anti-L. mexicana activity (IC₅₀s of compound 27a–c are 3.86, 3.39, and 3.45 μg/mL, respectively).

Isatin (CF: C₈H₅NO₂, MW: 147.13, 2,3-Indolinedione) is an orange-red single co-prism crystal. Nisha and his colleagues [30] synthesized the isatin–quinoline derivatives 28a–c (Figure 8) (Table 7) and determined their anti-trichomonas activity. Compounds 28a–c among them have effective anti-trichomonas action. At 50 μM, the growth inhibition of 28a–c was 98%, 100%, and 100%, respectively. 28a and 28c have IC₅₀s of 22.2 and 11.3 μM, respectively. 28a–28c had no cytotoxicity to PC-3 cells.

Licorice chalcone A (CF: C₂₁H₂₂O₄, MW: 338.4, ((2E)-3-[5-(1,1-dimethylprop-2-en-1-yl)-4-hydroxy-2-methoxyphenyl]-1-(4-hydroxyphenyl)prop-2-en-1-one)) is derived from the roots of Glycyrrhiza glabra and G. inflata. Coa and colleagues [31] synthesized quinoline–chalcone derivatives 29a–f and quinoline–chromone derivatives 30a–c (Figure 8) (Table 7), and evaluated their activity against Leishmania (Viannia) panamensis. Compounds 29a–f and 30a–c demonstrated activity against Leishmania (V) panamensis, while compounds 29b–e, and 30a–b demonstrated activity against Trypanosoma cruzi with EC₅₀ values less than 18 μg/mL. Compound 29f was the most active compound against Leishmania (V) panamensis and Trypanosoma cruzi, with EC₅₀s of 6.11 ± 0.26 and 4.09 ± 0.24 μg/mL. All hybrid compounds outperformed the anti-leishmanial drug meglumine antimoniate. Compounds 29d and 30b outperformed benznidazole, the current anti-trypanosomal drug; however, these compounds were toxic to mammalian U-937 cells.

Figure 8. The chemical structures of anti-parasitic compounds 27–30.

Matrine (CF: C₁₅H₂₄N₂O, MW: 248.37, (7aS,13aR,13bR,13cS)-dodecahydro-1H,5H,10H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10-one) is an alkaloid extracted from the dried roots, plants, and fruits of the legume Sophora flavescens by ethanol and other organic solvents. Huang and colleagues [32] synthesized quinoline–matrine derivatives 31a–u (Figure 9) (Table 7) and evaluated its acaricidal and insecticidal activities. Interestingly, all quinoline–matrine derivatives (save compound 31c) outperformed their antecedents in terms of acaricidal activity. In particular, compounds 31g, 31m, and 31r showed the most promising acaricidal action (the MR of compounds 31g, 31m, and 31r at 72 h are 37.1%, 37.1%, and 36.1%, respectively). It is worth noting that the introduction of chlorine atoms at the C-21 position of compound 31a–j is important for the acaricidal activity (the MR of compounds 31d (including 21-CH₃), 31f (including 21-F), 31h (including 21-Br), 31i (including 21-NH₂), and 31j (including 21-OH) at 72 h are 29.5%, 29.6%, 26.6%, 26.0%, and 26.9%, respectively; the MR of compound 31g (containing 21-Cl) at 72 h was 37.1%). The insertion of chlorine atoms on the benzoyl oxy group of compound 31k is required for acaricidal activity in compounds 31k–o. Compound 31r (having 3-Br on the benzoyl amino group) has a higher acaricidal efficacy than compounds 31p–t (31p, 31q, and 31s containing chlorine atoms on the benzoyl amino group). The findings suggested that these compounds may have antithrombotic hormone-like properties. All quinoline–matrine derivatives (31a–u) were more effective against insects than their antecedents. Compounds 31d–g, 31i, 31p, and 31s showed the most effective activity (the FMR of compounds 31d–g, 31i, 31p, and 31s are 65.5%, 62.1%, 65.5%, 69.0%, 62.1%, 65.5%, and 65.5%, respectively). The location of the methyl group is critical for insecticidal efficacy in compounds 31b–d. Compounds 31b (containing 19-CH₃) and 31d (containing 21-CH₃) have FMRs of 58.6% and 65.5%, respectively; compound 31c (containing 20-CH₃) has an FMR of 44.8%. For compounds 31a–j, the quinoline segment of 31a is the modified position, and the introduction of an appropriate group on the quinoline segment of 31a can lead to more effective derivatives, such as compounds 31d (containing 21-CH₃; FMR: 65.5%), 31e (containing 19-OCH₃; FMR: 62.1%), 31f (containing 21-F; FMR: 65.5%), 31g (containing 21-Cl; FMR: 69.0%), and 31i (containing 21-NH₂; FMR: 62.1%). Although the derivative 31k–o was created by inserting various benzoyl groups into compound 31j, it did not have the same insecticidal action as compound 31a. When R₂ is a 3- or 4-chlorine atom, the related compounds 31p and 31s have higher insecticidal action than 31a. Compound 31u (21-NHCH₃CO groups; 72 h FMR: 33.2%) showed more activity than compound 31i (21-NH₂ groups; 72 h FMR: 26.0%).

Wang and colleagues [33] synthesized 4-hydroxy-11-oxo-11H-chromoene [2,3-g] quinoline-3-carboxylic acid ethyl ester 32a–d (Figure 9) (Table 7) and tested their anti-coccidian activity. Compounds 32a–d demonstrated anticoccidial activity against Eimeria tenella with ACIs of 147, 123, 133, and 148, respectively.

Figure 9. The chemical structures of anti-parasitic compounds 31–32.

Roussaki and colleagues [34] synthesized quinolinone–chalcone derivatives 33–36 (Figure 10) (Table 7) and evaluated their biological activities against mammalian T. brucei and Leishmania infantis. Among them, the most effective is compound 33b (IC₅₀ = 2.6 ± 0.1 μM), followed by compounds 33g, 33c, 33f, and 33d (decreasing potency), all of which contain electron-donating substituents on the B ring of the chalcone group. The data analysis shows that the position and number of these groups contribute to the anti-parasitic properties of the compounds. For the most effective trypanosome agent, compound 33b, the electron-donating methyl substituent is located at the 2 position of the B ring, and its isomer, compound 33a, contains a methyl group at the 4 position, which does not affect the growth of trypanosome at a concentration of up to 10 μM. Similarly, compound 33d containing a single methoxy group at the 3 position of the B ring has lethality (IC₅₀ = 6.5 ± 0.1 μM). In contrast, the isomer chalcone containing the 4-methoxy group does not affect the growth of the parasite. The presence of two electron-abandoned substituents resulted in a slight increase in trypanosomal activity as follows: Compound 33f contains two methoxy groups at the 3 and 4 positions of the B ring, with an IC₅₀ value of 4.9 ± 0.2 μM, while compound 33c has an IC₅₀ value of 4.9 ± 0.1 μM, and its 3 and 4 positions contain a methoxy group and a hydroxyl group, respectively. The remaining insecticide chalcone, compound 33g, has a (di-tert-butyl) phenol substitute. Although it is the second most effective anti-trypanosomal structure in the chalcone series (IC₅₀ = 3.3 ± 0.1 μM), it shows high cytotoxicity (IC₅₀ ≈ 26 μM). For compounds 33b and 33f, analogues containing alkyl substituents on the amide nitrogen of the heterocyclic ring of the quinolinone molecule (compounds 35a–d) were synthesized. N-ethyl analogues 35a and 35b did not show growth inhibition against Brucella in the blood. Compounds 35c and 35d, N-benzyl analogues of chalcones, were less active against Brucella than non-alkyl compounds, although higher than N-ethyl analogues. These results indicate that the hydrogen of heterocyclic amide groups is important in the mechanism of these compounds. Similarly, by adding electron-withdrawing groups (-COOH, -CF_3, and -NO₂) (compounds 33h, 33i, and 33j) to the B ring of chalcone or extending the conjugated system between quinolinone and chalcone patterns (compounds 34a and 34b), the quinolinone–chalcone structure was changed in other parts. There was no effect on the growth of trypanosomes at a concentration of 10 μM. The a,b-unsaturated carbonyl system was modified by synthesizing the pyrazoline analogues 36a and 36b, significantly increasing anti-parasitic activity against B. haemolytic. The IC₅₀s of these two compounds were lower than that of the reference drug nifurtimox, so they were the most active against B. haemolytic among all the tested compounds in this work. Pyrazoline 36a (IC₅₀ = 1.46 ± 0.1 μM) can be considered a promising anti-parasitic compound because it has no cytotoxicity to THP1 cells. When a series of quinolinone–chalcone hybrids were screened against the astigmatic stage in larval cells, structures (compounds 33–34, 35a–b) were shown to affect the growth of parasites. The most potent compounds were 33g, 33a, and 33h, with IC₅₀s of 1.3 ± 0.1, 2.1 ± 0.6, and 3.1 ± 1.0 μM, respectively. Interestingly, the structure–activity relationship against L. infantum observed using compound series significantly differs from that against T. brucei, and many differences are directly opposite. For example, the shift of the methyl substituent from the 4 position (compound 33a) to the 2 position (compound 33b) or the methoxy group from the 4 position (compound 33e) to the 3 position (compound 33d) results in a significant decrease in insecticidal activity, which is different from the case of Brucella virus. In addition, the electronic properties of the substituents do not seem to play an important role in anti-Lishmaniasis activity as they do for Brucellosis as follows: Compound 33h with electron-withdrawing group trifluoromethyl (methyl isomer) at the 4 position of the B ring is the third most effective agent for infantile disease in this series, and derivatives containing-NO₂ and-COOH (compounds 33i and 33j) also affect infantile disease amastigotes. Why these conflicting SAR differences occur is unclear. This may reflect the following different locations of these parasites in mammalian hosts: Brucella is an extracellular pathogen found in the blood of the host, and larvae can invade and grow in the host’s macrophages, residing in an acidic compartment. In addition, this may only be due to the concentration range used in the screening as follows: many leishmaniasis compounds have IC₅₀s > 10 μM, which is the highest level used to combat Brucella. The N-alkylation of heterocyclic amide groups led to compounds with lower or slightly better anti-Lishmaniasis activity than non-alkylated analogues, indicating that the N-H group may be the key to anti-Lishmaniasis activity, which is also true in anti-filarial activity. Compared with chalcone analogue 9, pyrazoline 36a has lower activity against infantile lymphoma, while pyrazoline 36b, an analogue of chalcone 5, is the most active anti-Lishman disease agent among all tested compounds, with an IC₅₀ value of 0.71 μM. Notably, pyrazoline 36b showed the best anti-parasitic activity against both parasites. In order to evaluate their effects on mammalian cells, cytotoxicity tests were performed on differentiated THP-1 macrophages with all compounds. Among the most effective agents (IC₅₀ < 10 μM), compounds 33a, 33b, 33d, 33f, 33h, and 36a had no growth inhibitory effect on THP-1 cells at concentrations of 30 μM (33b, 33d, and 33f) or 50 μM (33a, 33h, and 36a), while the IC₅₀s of compounds 33c and 33g were about 20 μM. Due to problems related to the solubility of compounds in DMSO and other common solvents, the exact IC₅₀ cytotoxicity data cannot be determined. A comparison of efficacy against parasites and mammalian strains showed that pyrazoline 36a and chalcone 5 were the most effective trypanosome preparations, while chalcone analogue 36a was an interesting guide structure for L. infantum. In summary, compounds 36a and 36b have obvious anti-parasitic activity against T. brucei blood in vitro. Although pyrazoline 36b showed the best activity against both parasites and was the most effective compound among all the parasites tested in this work, its high cytotoxicity to mammalian cells prohibits further consideration as a lead compound. In contrast, pyrazoline 36a should be considered a drug to induce trypanosomiasis because of its high anti-parasitic activity and no cytotoxicity.

Pan and colleagues [35] synthesized coumarin derivatives 37–38 (Figure 10) (Table 7) and tested the nematicidal activity of these derivatives. Compounds 37 and 38 showed significant broad spectrum nematicidal activity. (The LC₅₀s for M. incognita, Ditylenchus destructor, Bursaphelenchus mucronatus, B. xylophilus, and Aphelenchoides besseyi of compound 37 were are 64.0, 52.9, 97.9, 103.2, and 95.2 μmol/L, respectively. The LC₅₀s for M. incognita, Ditylenchus destructor, Bursaphelenchus mucronatus, B. xylophilus, and Aphelenchoides besseyi of compound 38 were 42.4, 68.0, 77.8, 145.5, and 120.7 μmol/L, respectively).

Fraxinellone (CF: C₁₄H₁₆O₃, MW: 232.275, 7-dimethyl-3a,4,5,6-tetrahydro-2-benzofuran-1(3H)-one) is isolated from the root bark of the Brassica plant Dictamnus dasycarpus. Guo and colleagues [36] synthesized fraxinellone–quinoline derivative 39 (Figure 10) (Table 7) and tested the in vivo insecticidal activity of isolated Mycobacterium pre-3 instar larvae. Compound 39 showed more promising insecticidal activity than positive contrast (the M. separata on leaves mortality rate for 10 days, 25 days, and 35 days are 20.7%, 48.1%, and 63.0%, respectively).

Guo and colleagues [37] synthesized usnea acid quinoline derivative 40 (Figure 10) (Table 7) and tested its anti-T. gondii activity. Compound 40 had lower cytotoxicity and a higher selectivity index, indicating that its activity was superior to that of the lead drug and positive control drugs. The results of tachyzoite content assessment in mice abdomen showed that the compound 40 inhibition rate of abdominal tachyzoites in mice reached 55.2% (p < 0.01), 58.3% (p < 0.01), and 64.6% (p < 0.001), respectively, the numbers of tachyzoites were significantly reduced, respectively. At the same concentration, (+)-usnic acid and 40 inhibited tachyzoites more effectively than the positive control; moreover, compound 40 has better anti-T. The activity of Toxoplasma gondii is higher than the natural product (+)-usnic acid. The toxicity of compound 40 was further investigated by measuring the ALT and AST levels in the serum of KM mice. Compared with the normal group, the serum ALT level of the Toxoplasma-infected mice was significantly increased (p < 0.05). The serum ALT levels were significantly lower (p < 0.01) in the compound 40-treated group than in the (+)-usnic acid-treated group.

Dihydroartemisinin (CF: C₁₅H₂₄O₅, MW: 284.35, (4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo hexadecan-10-ol) is an artemisinin derivative that has a powerful and rapid killing impact on the red internal stage of Plasmodium and can reduce clinical attacks and symptoms swiftly. Deng and colleagues [38] synthesized dihydroartemisinin quinoline derivatives 41–42 (Figure 10) (Table 7) and evaluated their anti-Toxoplasma activity. Compounds 41 and 42a–c were more effective against Toxoplasma than dihydroartemisinin (The selectivity index of compounds 41a and 42a–c was 0.84, 1.02, 0.43, and 1.02).

Figure 10. The chemical structures of anti-parasitic compounds 33–42.

Table 7. Quinoline derivatives with anti-parasitic activity.

Compd.	Activity	Target	Origin	Ref
27a	anti-T. brucei IC₅₀ = 0.37 μg/mL anti-L. Mexicana IC₅₀ = 3.86 μg/mL	-	synthetic	[29]
27b	anti-T. brucei IC₅₀ = 0.39 μg/mL anti-L. Mexicana IC₅₀ = 3.39 μg/mL	-	synthetic	[29]
27c	anti-T. brucei IC₅₀ = 0.40 μg/mL anti-L. Mexicana IC₅₀ = 3.45 μg/mL	-	synthetic	[29]
28a	anti-trichomonas IC₅₀ = 22.2 μM	-	synthetic	[30]
28b	-	-	synthetic	[30]
28c	anti-trichomonas IC₅₀ = 11.3 μM	-	synthetic	[30]
29a	Leishmanicidal EC₅₀ = 11.79 μg/mL Trypanocidal EC₅₀ = 35.08 μg/mL	-	synthetic	[30]
29b	Leishmanicidal EC₅₀ = 6.24 μg/mL Trypanocidal EC₅₀ = 17.62 μg/mL	-	synthetic	[31]
29c	Leishmanicidal EC₅₀ = 12.37 μg/mL Trypanocidal EC₅₀ = 15.79 μg/mL	-	synthetic	[31]
29d	Leishmanicidal EC₅₀ = 8.53 μg/mL Trypanocidal EC₅₀ = 37.61 μg/mL	-	synthetic	[31]
29e	Leishmanicidal EC₅₀ = 16.41 μg/mL Trypanocidal EC₅₀ = 15.12 μg/mL	-	synthetic	[31]
29f	Leishmanicidal EC₅₀ = 22.0 μg/mL Trypanocidal EC₅₀ = 54.95 μg/mL	-	synthetic	[31]
30a	Leishmanicidal EC₅₀ = 6.11 μg/mL Trypanocidal EC₅₀ = 4.09 μg/mL	-	synthetic	[31]
30b	Leishmanicidal EC₅₀ = 16.18 μg/mL Trypanocidal EC₅₀ > 20 μg/mL	-	synthetic	[31]
30c	Leishmanicidal EC₅₀ = 2.36 μg/mL Trypanocidal EC₅₀ > 2 μg/mL	-	synthetic	[31]
31a	Corrected mortality rate 48 h FMR 8.7% 72 h FMR 32.7%	-	synthetic	[32]
31b	Corrected mortality rate 48 h FMR 7.8% 72 h FMR 28.0%	-	synthetic	[32]
31c	Corrected mortality rate 48 h FMR 2.8% 72 h FMR 19.2%	-	synthetic	[32]
31d	Corrected mortality rate 48 h FMR 7.5% 72 h FMR 29.5%	-	synthetic	[32]
31e	Corrected mortality rate 48 h FMR 6.9% 72 h FMR 24.4%	-	synthetic	[32]
31f	Corrected mortality rate 48 h FMR 6.9% 72 h FMR 29.6%	-	synthetic	[32]
31g	Corrected mortality rate 48 h FMR 7.7% 72 h FMR 37.1%	-	synthetic	[32]
31h	Corrected mortality rate 48 h FMR 6.3% 72 h FMR 26.6%	-	synthetic	[32]
31i	Corrected mortality rate 48 h FMR 5.0% 72 h FMR 26.0%	-	synthetic	[32]
31j	Corrected mortality rate 48 h FMR 6.5% 72 h FMR 26.9%	-	synthetic	[32]
31k	Corrected mortality rate 48 h FMR 3.8% 72 h FMR 26.5%	-	synthetic	[32]
31l	Corrected mortality rate 48 h FMR 2.9% 72 h FMR 20.6%	-	synthetic	[32]
31m	Corrected mortality rate 48 h FMR 15.5% 72 h FMR 37.1%	-	synthetic	[32]
31n	Corrected mortality rate 48 h FMR 7.2% 72 h FMR 30.7%	-	synthetic	[32]
31o	Corrected mortality rate 48 h FMR 5.9% 72 h FMR 28.7%	-	synthetic	[32]
31p	Corrected mortality rate 48 h FMR 9.6% 72 h FMR 30.9%	-	synthetic	[32]
31q	Corrected mortality rate 48 h FMR 3.2% 72 h FMR 22.5%	-	synthetic	[32]
31r	Corrected mortality rate 48 h FMR 9.5% 72 h FMR 36.1%	-	synthetic	[32]
31s	Corrected mortality rate 48 h FMR 6.4% 72 h FMR 26.7%	-	synthetic	[32]
31t	Corrected mortality rate 48 h FMR 4.8% 72 h FMR 26.6%	-	synthetic	[32]
31u	Corrected mortality rate 48 h FMR 8.6% 72 h FMR 33.2%	-	synthetic	[32]
32a	ACI = 147	-	synthetic	[33]
32b	ACI = 123	-	synthetic	[33]
32c	ACI = 133	-	synthetic	[33]
32d	ACI = 148	-	synthetic	[33]
33a	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 2.1 μM	FRD	synthetic	[34]
33b	T. brucei IC₅₀ = 2.6 μM L. infantum IC₅₀ > 50 μM	FRD	synthetic	[34]
33c	T. brucei IC₅₀ = 4.9 μM L. infantum IC₅₀ = 11.5 μM	FRD	synthetic	[34]
33d	T. brucei IC₅₀ = 6.5 μM L. infantum IC₅₀ = 28.4 μM	FRD	synthetic	[34]
33e	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 12.7 μM	FRD	synthetic	[34]
33f	T. brucei IC₅₀ = 4.9 μM L. infantum IC₅₀ = 7.5 μM	FRD	synthetic	[34]
33g	T. brucei IC₅₀ = 3.3 μM L. infantum IC₅₀ = 1.3 μM	FRD	synthetic	[34]
33h	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 3.1 μM	FRD	synthetic	[34]
33i	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 26.9 μM	FRD	synthetic	[34]
33j	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 18.4 μM	FRD	synthetic	[34]
34a	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ > 50 μM	FRD	synthetic	[34]
34b	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 20.0 μM	FRD	synthetic	[34]
35a	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ = 24.8 μM	FRD	synthetic	[34]
35b	T. brucei IC₅₀ > 10 μM L. infantum IC₅₀ > 50 μM	FRD	synthetic	[34]
35c	T. brucei IC₅₀ = 6.17 μM L. infantum IC₅₀ > 25 μM	FRD	synthetic	[34]
35d	T. brucei IC₅₀ = 5.68 μM L. infantum IC₅₀ > 25 μM	FRD	synthetic	[34]
36a	T. brucei IC₅₀ = 1.46 μM L. infantum IC₅₀ = 13.46 μM	FRD	synthetic	[34]
36b	T. brucei IC₅₀ = 1.43 μM L. infantum IC₅₀ = 0.71 μM	FRD	synthetic	[34]
37	M. incognita LC₅₀ = 64.0 μmol/L Ditylenchus destructor LC₅₀ = 52.9 μmol/L Bursaphelenchus mucronatus LC₅₀ = 97.9 μmol/L B. xylophilus LC₅₀ = 103.2 μmol/L Aphelenchoides besseyi LC₅₀ = 95.2 μmol/L	-	synthetic	[35]
38	M. incognita LC₅₀ = 42.4 μmol/L Ditylenchus destructor LC₅₀ = 68.0 μmol/L Bursaphelenchus mucronatus LC₅₀ = 77.8 μmol/L B. xylophilus LC₅₀ = 145.5 μmol/L Aphelenchoides besseyi LC₅₀ = 120.7 μmol/L	-	synthetic	[35]
39	M. separata on leaves mortality rate 10 days 20.7% 25 days 48.1% 35 days 63.0%	-	synthetic	[36]
40	inhibition rate of abdominal tachyzoites in mice 55.2% (p < 0.1), 58.3% (p < 0.01) 64.6% (p < 0.001)	-	synthetic	[37]
41	selectivity index 0.84	TgCDPK1	synthetic	[38]
42a	selectivity index 1.02	TgCDPK1	synthetic	[38]
42b	selectivity index 0.43	TgCDPK1	synthetic	[38]
42c	selectivity index 1.02	TgCDPK1	synthetic	[38]

Summary: The anti-T.brucei activity of Cinchonasine derivative 27a was the strongest, and the IC₅₀ value was 0.37 μg/mL. The anti-L.mexicana activity of derivative 27b was the strongest, and the IC₅₀ value was 3.39 μg/mL.

The EC₅₀ values of compound 29f against Leishmania (V) panamensis and Trypanosoma cruzi were 6.11 and 4.09 μg/mL, respectively.

The quinolinone–chalcone derivatives 36a and 36b showed the strongest inhibitory effect on T.brucei, with IC₅₀ values of 1.46 and 1.43 μM. 36a has no obvious cytotoxicity to THP1 cells and is an anti-parasitic compound with development value. Compounds 42a and 42c were more effective against Toxoplasma than dihydroartemisinin (The selectivity index of compounds 42a was 1.02). The anti-parasitic activity of natural products was enhanced by adding quinoline to natural products; however, the mechanism of action of these compounds has not been studied, so these compounds need further study.

3.8. Antimalarial Activity

Artemisinin (CF: C₁₅H₂₂O₅, MW: 282.34, (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-Benzodixepin-10-one) is mostly derived by direct extraction from Artemisia annua or by extracting artemisinic acid from Artemisia annua and then semi-synthetically obtaining it. Lombard and colleagues [39] synthesized two quinoline–artemisinin derivatives 43 and 44 (Figure 11) (Table 8) and evaluated their antimalarial activity. The in vivo anti-plasma parasite activity of hybrid dimers 43 and 44 was stronger than the positive control, with in vitro IC₅₀s of 8.7 and 29.5 μM against the 3D7 strain, respectively.

Raj and colleagues [40] synthesized a series of piperazine-coupled 7-chloroquinoline–isatin derivatives 45a–e (Figure 11) (Table 8), and their antimalarial and anti-chloroquine activities against Plasmodium falciparum were evaluated. However, compounds 45a–e have shown strong antimalarial activity with IC₅₀s of 1.12, 1.17, 0.27, 0.81, and 0.36 μM, respectively. Unfortunately, all of the compounds had lower activities than the positive control.

Raj and colleagues [41] performed the synthesis and antimalarial activity of a 1H-1,2,3-triazole-tethered 7-chloroquinoline–isatin derivatives 46a–j (Figure 11) (Table 8). Compounds 46a–j have longer alkyl chains between the 7-chloroquinoline and isatin groups and have better anti-plasma action. Unfortunately, the IC₅₀s of the tested compounds 46a–j were all greater than 1 μM, which was less effective than the positive control or artemisinin.

Nisha and colleagues [42] synthesized a series of β-amino alcohol-linked 4-aminoquinoline–indigo derivatives 47a–c (Figure 11) (Table 8) and evaluated their activity against CQ-resistant P. falciparum W2. The most active compounds were 47b–c, with IC₅₀s of 11.8 and 13.5 μM, respectively.

Videnović and colleagues [43] synthesized 4-amino-7-chloroquinoline (4,7-ACQ) bile salt derivative 48 (Figure 11) (Table 8) and determined its antimalarial activity. Compound 48 demonstrated the highest antimalarial activity, with a 95% inhibition rate and a Ki of 0.103 μM.

Figure 11. The chemical structures of antimalarial and anticancer compounds 43–48.

Leverrier and colleagues [44] synthesized cinchona–alkaloid derivatives 49–50 (Figure 12) (Table 8) and determined their in vitro activity against Trypanosoma brucei. Compounds 49a–b and 50a–b emerged as the most promising anti-Trypanosoma brucei due to their low cytotoxicity and IC₅₀s of 1.47, 0.64, 0.69, and 0.61 μM, respectively.

1,2,3,4-Tetrahydro-β-carbolines (THβCs) (CF: C₁₁H₁₂N₂, MW: 172.226, 1,2,3,4-tetrahydro-9h-pyrido[3,4-b]indole) represent a class of privileged structural motifs found in many pharmacologically active natural compounds possessing potential anticancer and antimalarial activities. Sharma and colleagues [45] synthesized 1H-1,2,3-triazole/hydrazole-integrated tetrahydro-β-carboline-4-aminoquinoline compounds 51a–f, 52a–h, and 53a–b (Figure 12) (Table 8) and evaluated their activity against the chloroquine-resistant (CQ) strain of Plasmodium falciparum W2. Although all compounds were not as active as the positive control medication, including the quinoline nucleus considerably increased the antimalarial efficacy of the THC nucleus. The activity of the synthesized conjugates depends on the nature of the substitution at the C-1 position of the THC nucleus, the type of function introduced as a linker, and the length of the alkyl chain, according to the structure–activity relationship (SAR). An analysis of the SAR of 1H-1,2,3-triazole tethered THC-4-aminoquinoline conjugates revealed an increase in the antimalarial activity with the introduction of flexible alkyl chains on the aminoquinoline core, as evidenced by the scaffolds 51c–f being more active than compounds 51a–b (The IC₅₀s of compounds 51a–b are 4.02 μM, 9.28 μM). The antimalarial activity of the aliphatic hydrazide-linked conjugates 52a–h increased with increasing alkyl chain length, although the type of the substituent at the C-1 position of THC did not appear to alter the activity profile. Interestingly, replacing the alkyl chain with an aryl core enhanced antimalarial activity, as seen by compound 53a, which has an IC₅₀ of 0.61 μM. The antimalarial activity of the -carboline and quinolinyl precursors used in this synthesis was also investigated. Compounds 53a–b (acyl hydrazide precursors) and 51c, 51e (1H-12,3-triazole-like precursors) were tested on mammalian Vero cells to determine if the observed activity was due to inherent antimalarial activity or cytotoxicity. The 1H-1,2,3-triazole-linked conjugates 51c and 51e were clearly non-cytotoxic, with SI > 300, whereas the acyl hydrazide-linked compounds 53a–b were somewhat cytotoxic to mammalian Vero cells. The most potent and non-cytotoxic compound 51e exhibited the best properties, including a C-1 unsubstituted THC core, a 1H-1,2,3-triazole core, and propyl as a flexible linker, with an IC₅₀ of 0.50 μM and a selectivity index of 495.76.

Vinindwa and colleagues [46] synthesized chalcone–quinoline derivatives 54a–o (Figure 12) (Table 8) and evaluated their antimalarial activity. With IC₅₀s ranging from 0.10 to 4.45 μM, all compounds showed potent activity against the Plasmodium falciparum NF54 sensitive strain. The fluorine-substituted molecular derivatives 54d, 54h, and 54n displayed higher activity than the unsubstituted molecular derivative 54a (IC₅₀ = 1.67 μM), suggesting the relevance of the electronic effect imparted by the more electronegative fluorine atoms. Other halogens with similar trends included bromine 54c (IC₅₀ = 0.10 μM), chlorine 54e (IC₅₀ = 0.10 μM), and methoxy 54f (IC₅₀ = 0.11 μM). The most active compounds were 54c, 54e, and 54f, with IC₅₀s of 0.10, 0.10, and 0.11 μM, respectively. The inhibitory properties of the compounds against the multidrug-resistant K1 strain of Plasmodium falciparum were investigated further. Compound 54f’s resistivity index RI = 5.36 (IC₅₀ = 0.59 μM) was roughly double that of the positive control, which was the leading compound in this study. Compounds 54c and 54e, on the other hand, displayed poor activity against the K1 strain, with IC₅₀s of 2.97 and 6 μM, respectively. Compounds with three methylene (n = 3) as linkers had higher efficacy against Plasmodium falciparum than compounds with two methylene (n = 2). Compared to compound 54i (n = 2), the addition of an extra CH₂ group (n = 3) in compound 54f enhanced its activity by nearly five times, while compound 54d (n = 2 IC₅₀ = 0.28 μM) increased by two times. Furthermore, practically all molecular derivatives 54b–f and 54g–j with three methylene linkers are the most active in the series, with IC₅₀s ranging from 0.10 to 0.86 μM. Compounds 54b and 54l, which have methyl groups at the para position and have the same activity (The IC₅₀s were 0.37 and 0.39 μM, respectively), show no effect on activity with smaller polarity. Compounds 54k and 54m have poor activity and contain 2-furanyl and ferrocenyl aromatic rings, demonstrating the relevance of chalcone units in the overall activity of the molecule. Most compounds were insoluble except for compounds 54b, 54i, 54j, 54l, and 54o, with IC₅₀ values less than 5 μM.

Flavonoids are secondary plant metabolites that are frequently found in nature. Flavonoids are a yellow pigment formed from a core of flavonoids (2-phenylchromones), which includes flavonoid isomers and their hydrogenation and reduction products, such as C6-C3-C6. Rodrigues and colleagues [47] synthesized the flavonoid quinoline derivative 55 (Figure 12) (Table 8) and determined its antimalarial activity. Compound 55 was tested in vitro for antimalarial activity against the chloroquine-resistant Plasmodium falciparum W2 strain. Compound 55 had moderate antimalarial activity, with an IC₅₀ of 5.17 μM.

Figure 12. The chemical structures of antimalarial compounds 49–55.

Table 8. Quinoline derivatives with antimalarial activity.

Compd.	Activity	Origin	Ref
43	Anti-plasma parasite IC₅₀ = 8.7 μM	synthetic	[39]
44	Anti-plasma parasite IC₅₀ = 29.5 μM	synthetic	[39]
45a	Antimalarial activity IC₅₀ = 1.12 μM	synthetic	[40]
45b	Antimalarial activity IC₅₀ = 1.17 μM	synthetic	[40]
45c	Antimalarial activity IC₅₀ = 0.27 μM	synthetic	[40]
45d	Antimalarial activity IC₅₀ = 0.81 μM	synthetic	[40]
45e	Antimalarial activity IC₅₀ = 0.36 μM	synthetic	[40]
46a	Antimalarial activity IC₅₀ > 5 μM	synthetic	[41]
46b	Antimalarial activity IC₅₀ > 5 μM	synthetic	[41]
46c	Antimalarial activity IC₅₀ > 5 μM	synthetic	[41]
46d	Antimalarial activity IC₅₀ > 5 μM	synthetic	[41]
46e	Antimalarial activity IC₅₀ > 5 μM	synthetic	[41]
46f	Antimalarial activity IC₅₀ = 3.07 μM	synthetic	[41]
46g	Antimalarial activity IC₅₀ = 2.30 μM	synthetic	[41]
46h	Antimalarial activity IC₅₀ = 1.37 μM	synthetic	[41]
46i	Antimalarial activity IC₅₀ = 1.73 μM	synthetic	[41]
46j	Antimalarial activity IC₅₀ = 1.63 μM	synthetic	[41]
47a	Antimalarial activity IC₅₀ = 24.9 nM	synthetic	[42]
47b	Antimalarial activity IC₅₀ = 11.8 nM	synthetic	[42]
47c	Antimalarial activity IC₅₀ = 13.5 nM	synthetic	[42]
48	Antimalarial activity Ki = 0.103 μM	synthetic	[43]
49a	Anti-Trypanosoma brucei IC₅₀ = 1.47 μM	synthetic	[44]
49b	Anti-Trypanosoma brucei IC₅₀ = 0.64 μM	synthetic	[44]
50a	Anti-Trypanosoma brucei IC₅₀ = 0.69 μM	synthetic	[44]
50b	Anti-Trypanosoma brucei IC₅₀ = 0.61 μM	synthetic	[44]
51a	Antimalarial activity IC₅₀ = 9.28 μM	synthetic	[45]
51b	Antimalarial activity IC₅₀ = 4.02 μM	synthetic	[45]
51c	Antimalarial activity IC₅₀ = 0.86 μM	synthetic	[45]
51d	Antimalarial activity IC₅₀ = 0.93 μM	synthetic	[45]
51e	Antimalarial activity IC₅₀ = 0.49 μM	synthetic	[45]
51f	Antimalarial activity IC₅₀ = 1.37 μM	synthetic	[45]
52a	Antimalarial activity IC₅₀ = 4.4 μM	synthetic	[45]
52b	Antimalarial activity IC₅₀ = 1.73 μM	synthetic	[45]
52c	Antimalarial activity IC₅₀ = 5.0 μM	synthetic	[45]
52d	Antimalarial activity IC₅₀ = 3.1 μM	synthetic	[45]
52e	Antimalarial activity IC₅₀ = 2.0 μM	synthetic	[45]
52f	Antimalarial activity IC₅₀ = 3.1 μM	synthetic	[45]
52g	Antimalarial activity IC₅₀ = 3.4 μM	synthetic	[45]
52h	Antimalarial activity IC₅₀ = 2.2 μM	synthetic	[45]
53a	Antimalarial activity IC₅₀ = 1.8 μM	synthetic	[45]
53b	Antimalarial activity IC₅₀ = 0.61 μM	synthetic	[45]
54a	Antimalarial activity IC₅₀ = 0.45 μM	synthetic	[46]
54b	Antimalarial activity IC₅₀ = 0.37 μM	synthetic	[46]
54c	Antimalarial activity IC₅₀ = 0.10 μM	synthetic	[46]
54d	Antimalarial activity IC₅₀ = 0.28 μM	synthetic	[46]
54e	Antimalarial activity IC₅₀ = 0.10 μM	synthetic	[46]
54f	Antimalarial activity IC₅₀ = 0.11 μM	synthetic	[46]
54g	Antimalarial activity IC₅₀ = 0.32 μM	synthetic	[46]
54h	Antimalarial activity IC₅₀ = 0.86 μM	synthetic	[46]
54i	Antimalarial activity IC₅₀ = 0.49 μM	synthetic	[46]
54j	Antimalarial activity IC₅₀ = 0.50 μM	synthetic	[46]
54k	Antimalarial activity IC₅₀ = 4.45 μM	synthetic	[46]
54l	Antimalarial activity IC₅₀ = 0.39 μM	synthetic	[46]
54m	Antimalarial activity IC₅₀ = 1.53 μM	synthetic	[46]
54n	Antimalarial activity IC₅₀ = 0.57 μM	synthetic	[46]
54o	Antimalarial activity IC₅₀ = 0.69 μM	synthetic	[46]
55	Antimalarial activity IC₅₀ = 5.17 μM	synthetic	[47]

Summary: Quinoline has always been a key scaffold for antimalarial research. Many antimalarial drugs, such as chloroquine and primaquine, contain a quinoline structure. With the increasing resistance of Plasmodium falciparum, there is an urgent need to develop new strategies and new antimalarial compounds to overcome the growing resistance. These include drug combination, drug reuse, and the use of chemical sensitizers (resistance reversal agents) and the development of new analogues, both of which involve the synthesis of new quinoline analogues.

7-chloroquinoline–isatin derivatives 45c showed strong antimalarial activity with IC₅₀ of 0.27 μM. Compounds 54c and 54e also showed significant antimalarial activity with IC₅₀ of 0.10 μM.

The introduction of quinoline by isatin and chalcone can significantly increase antimalarial activity. Unfortunately, the antimalarial mechanism of these compounds has not been studied.

3.9. Antibacterial Activity

Paul and colleagues [48] synthesized a sulfur-linked quinoline derivative 56–57 (Figure 13) (Table 9) and preliminarily evaluated its in vitro antibacterial activity against Gram-positive Staphylococcus aureus (ATCC 11632) and Gram-negative Escherichia coli (ATCC 25922), and antifungal activity against Candida albicans (ATCC 90028). The results showed that most compounds had moderate to good antibacterial and antifungal activities (6.25–50.0 μg/mL). Compounds 56b–h and 57a–b have moderate to good activity, and the inhibition zone is equivalent to that of the positive control against Escherichia coli. Compared with the positive control, compounds 56a, 56c, 56d, 56e, 56f, 56g, 56h, and 57a showed moderate activity against S.aureus. In the antifungal activity evaluation, compared with the positive control, compounds 56a, 56c, 56e, 56f, 56g, 56h, 57a, and 57b showed moderate activity against Candida albicans. Nitro, brominated, or chlorinated compounds have comparable activity to standard drugs.

Patel and colleagues [49] synthesized a series of novel 7-hydroxy-9- (furo [2,3-b] quinoline-2-yl) 6H-benzo [c] coumarin derivatives 58a–l (Figure 13) (Table 9) against two Gram-positive bacteria Staphylococcus aureus (MTCC 96) and Bacillus subtilis (MTCC 441) and two Gram-negative bacteria Escherichia coli (MTCC 443) and Salmonella (MTCC 98) in vitro antibacterial activity. The antifungal activities of Candida albicans (MTCC 227) and Aspergillus niger (MTCC 282) were also evaluated in vitro. Ampicillin, chloramphenicol, and norfloxacin were used as standard antimicrobial agents. Glibenclamide and nystatin were used as standard antifungal agents. Compared with standard antimicrobial agents, all compounds are active against Gram-negative bacteria and fungi. Upon evaluating the antimicrobial activity data, it was observed that compounds 58c, 58h, and 58k (MIC = 200 μg/mL) showed good activity compared to ampicillin (MIC = 250 μg/mL) against Gram-positive bacteria B. subtilis. The compounds 58b, 58d, 58e, 58f, 58g, and 58l (MIC = 250 μg/mL) exerted equipotent activity against Gram-positive bacteria B. subtilis. against S. aureus, Compounds 58j and 58l (MIC = 100 μg/mL) and 58d, 58e, and 58k (MIC = 125 μg/mL) exhibited moderate activity compared to ampicillin (MIC = 250 μg/mL) against Gram-positive bacteria S. aureus. Compounds 58b and 58g (MIC = 200 μg/mL) showed better activity compared to ampicillin (MIC = 250 μg/mL) against Gram-positive bacteria S. aureus. Compounds 58a, 58c, 58h, and 58i (MIC = 250 μg/mL) were found equipotent to ampicillin (MIC = 250 μg/mL) against Gram-positive bacteria S. aureus. Compounds 58c, 58d, 58f, and 58j (MIC = 62.5 μg/mL) exhibited outstanding activity compared to ampicillin (MIC = 100 μg/mL) against Gram-negative bacteria E. coli and S. typhi, respectively. The compounds 58a, 58f, 58g, 58h, and 58k (MIC = 100 μg/mL) and compounds 58a, 58c, 58d, and 58j (MIC = 100 μg/mL) were found equipotent compared to ampicillin (MIC = 100 μg/mL) against E. coli and S. typhi, respectively. Compound 58i and 58g (MIC = 200 μg/mL) and compounds 58c, 58f, and 58h (MIC = 250 μg/mL) were found to be more active against C. albicans compared to griseofulvin (MIC = 500 μg/mL). Compounds 58a and 58b (MIC = 500 μg/mL) were found equipotent to griseofulvin (MIC = 500 μg/mL) against C. albicans. It is perceived from the antimicrobial data that almost all the tested derivatives 58a–l was found to be potent against the Gram-positive bacterial strains. Among all the tested compounds, the compounds 58c, 58d, 58f, and 58j were found to be more efficient members of the series. Most synthesized compounds were active against Gram-positive bacteria viz. Bacillus subtilis (MTCC 441) and Staphylococcus aureus (MTCC 96), Gram-negative bacteria viz. Escherichia coli (MTCC 443) and Salmonella typhi (MTCC 98). Some of the synthesized compounds were found sufficiently potent to inhibit fungal pathogen viz. Candida albicans (MTCC 227).

Curcumin (CF: C₂₁H₂₀O₆, MW: 368.39, (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) is a diketone compound extracted from the rhizomes of some plants in the Zingiberaceae and Araceae, and is a very rare pigment with diketone structure in the plant kingdom. Subhedar and colleagues [50] synthesized quinoline–curcumin derivatives 59–60 (Figure 13) (Table 9), and evaluated their anti-tuberculosis activity against MTB and M. bovis BCG in vitro. Rifampicin as a positive control. Overall, the synthesized compounds showed excellent selectivity against M. bovis BCG compared to the MTB strain. Among the synthesized quinolinyl monocarbonyl curcumin analogues, compounds 59a, 59c, and 60a–c with MIC⁹⁰ range of 7.8–27.9 μg/mL were active against dormant MTB strains, while compounds 59b–d, 60a–c, and 60d with MIC₉₀ range of 2.7–27.2 μg/mL were active against dormant M. bovis BCG strains were active. The biological evaluation results reveal that, the activity was considerably affected by introducing various substituents on the quinoline ring and N-methylation of piperidinone scaffold. From the compounds 59a–d, compound 59a and 59c showed moderate antitubercular activity with MIC90 value 25.5 and 27.9 µg/mL, respectively, against dormant MTB strain. The remaining analogues from the series does not display significant antitubercular activity against dormant MTB strain with MIC₉₀ values > 30 µg/mL. N-Methylpiperidinone-based analogues 60a–d, particularly, compounds 60a (MIC₉₀ value 26.5 µg/mL) and 60b (MIC₉₀ value 20.0 µg/mL), showed good to moderate antitubercular activity against dormant MTB strain. In particular, compound 60c showed excellent antitubercular activity against dormant MTB strain with MIC90 value 7.8 µg/mL. Hence, among all the synthesized analogues, the only compounds 59a, 59c, and 60a–c showed moderate to excellent antitubercular activity against dormant MTB strain. From the analogues 59a–d, compound 59b showed excellent antitubercular activity with MIC₉₀ value 2.7 µg/mL against dormant M. bovis BCG strain. Compound 59c showed moderate antitubercular activity with MIC90 value 27.2 µg/mL against dormant M. bovis BCG strain. Compound 59d showed promising antitubercular activity against dormant M. bovis BCG strain with MIC₉₀ value 9.2 µg/mL. From the series 60a–d, compound 60a showed excellent antitubercular activity with a MIC90 value 7.3 µg/mL against dormant M. bovis BCG strain. Compound 60b and 60d showed good to moderate antitubercular activity with MIC90 value 15.4 and 21.5 µg/mL, respectively, against dormant M. bovis BCG strain. Compound 60c showed promising antitubercular activity against dormant M. bovis BCG strain with MIC₉₀ value 9.4 µg/mL. In short, quinoline-based monocarbonyl curcumin analogues 59b–d, 60a–d showed good to excellent antitubercular activity against dormant M. bovis BCG strain.

Aurone (CF: C₁₅H₁₀O₂, MW: 222.24, 2-Benzylidene-3(2H)-benzofuranone) is a heterocyclic compound of the flavonoid family with a benzofuran moiety linked to a benzylidene group at position C-2. Campaniço and colleagues [51] synthesized azaaurones derivative 61 (Figure 13) (Table 9) and evaluated its anti-mycobacterial MDR- and XDR-TB activity. Compound 61 showed excellent activity against clinically isolated MDR and XDR-TB with MIC₉₉ values of 0.649 and 0.736 μM, respectively.

Kumar and colleagues [52] synthesized aurones quinoline derivatives 62a–f (Figure 13) (Table 9) and evaluated their antibacterial and antifungal activities against Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Aspergillus fumigatus, Candida albicans, and Fusarium oxysporum. All test compounds showed antibacterial activity against Gram-positive test strains; however, only compounds 62c and 62e showed antibacterial activity against Gram-negative test strains (Klebsiella pneumoniae); both MIC values are 0.625 mg/mL. In addition, only compounds 62a–b, 62d, and 62f showed activity against the acid-fast microbial strain (MIC range of 0.625–0.078 mg/mL). This different antimicrobial behavior may be due to the differences in their composition and cell membrane structure in different microbial strains since the peptidoglycan layer of Gram-positive bacteria and the phospholipid membrane of Gram-negative bacteria interact differently with different antimicrobial agent molecules.

Sabatini and colleagues [53] synthesized the quinoline derivatives 63–64 (Figure 13) (Table 9) from flavonoids and evaluated the function of EPI. The results showed that compounds 63 and 64 exhibited good antibacterial activity (SA-1199B inhibited EtBr efflux > 65% at 50 μM concentration).

Wang and colleagues [54] synthesized 3-(iso)quinolinyl-4-chromenone derivatives 65–66 (Figure 13) (Table 9) and evaluated their antifungal activity. Bioassay data showed that 3-quinolinyl-4-chromenone 65 showed significant in vitro activity against Sclerotinia sclerotiorum, Vibrio marcescens, and grey mould with EC₅₀ values of 3.65, 2.61, and 2.32 mg/L, respectively. 3-isoquinolinyl-4-chrome none 66 showed excellent in vitro activity against Sclerotinia sclerotiorum with an EC₅₀ value of 1.94 mg/L, which was close to the commercial fungicide chlorothalonil (EC₅₀ = 1.57 mg/L), but lower than Boscard (EC₅₀ = 0.67 mg/L). For V. mali and B. cinerea, the activity of 3-isoquinolinyl-4-chrome none 66 (EC₅₀ = 1.56, 1.54 mg/L) was significantly higher than that of chlorothalonil (EC₅₀ = 11.24, 2.92 mg/L). In addition, in vivo experiments showed that compounds 65 and 66 showed 88.24% and 94.12% inhibition against grey mould at 50 mg/L, compared to 76.47% and 97.06% inhibition by the positive controls chlorothalonil and boscalid, respectively. Physiological and biochemical studies suggest that the main mechanism of action of compounds 65 and 66 on S. sclerotiorum and B. cinerea may involve altering the morphology and increasing the permeability of cell membranes of A. aurantium.

Figure 13. The chemical structures of antibacterial compounds 56–66.

Gogoi and colleagues [55] synthesized the A- and D-ring-fused steroid quinolines derivatives 67a–j (Figure 14) (Table 9) and evaluated their antibacterial and antifungal activities. Cystine was used as a standard drug against fungi, and gentamicin sulfate was used against bacteria. The results showed that compound 67a did not exert potent inhibitory activity against all bacterial strains tested. Methoxy derivative 67c showed an inhibitory effect against bacterial strains Pseudomonas aeruginosa, while compounds 67e, 67g–h, and 67j showed significant inhibition against bacterial strains Staphylococcus aureus and Bacillus subtilis. These results suggest that the substituents in the quinoline molecules of compounds 67a and 67f, as well as the backbone structure, play an important role in the inhibitory activity of bacterial strains. For the fungal strain A. niger, only the tested compound 67a showed a strong inhibition (MIC = 22 μg/mL), while compounds 67e and 67g–h showed only moderate inhibition. In contrast, most of the tested compounds 67e–h and 67j showed a strong inhibition of the growth of the fungal strain C. albicans (MIC values arranged 13–19 μg/mL). Compounds 67b, 67d, and 67i were not effective against any of the tested strains. Furthermore, the determination of MICs and MFCs of the active compounds showed that compound 67e showed maximum activity against most of the tested strains with 21 μg/mL for S. aureus, 19 μg/mL for B. subtilis, 23 μg/mL for C. albicans and 28 μg/mL for C. niger. It is evident from the data that compounds 67c and 67f against Pseudomonas aeruginosa showed very good antibacterial activity, almost similar to the standard drug gentamicin sulfate. Similarly, 67e, 67g–h, and 67j showed inhibitory activity against the bacterial strains Bacillus subtilis (MIC values arranged 12–22 μg/mL) and Staphylococcus aureus (MIC values arranged 10–23 μg/mL), indicating that these compounds are promising antimicrobial compounds for further investigation.

Balaji and colleagues [56] synthesized a series of quinoline–coumarin derivatives 68a–g (Figure 14) (Table 9) and evaluated the in vitro antibacterial activity against Gram (+) and Gram (−) bacteria, such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Meloidogyne litoralis, and Bacillus subtilis. Compounds possessing methyl, methoxy, and fused aryl rings, such as 68c, 68d, and 68g, at C-8 of quinoline ring showed better activity than their standard drug streptomycin against Escherichia coli (all MIC values are 6.25 μg/mL). Similarly, compounds 68d and 68g showed better activity against P. aeruginosa (both MIC values are 6.25 μg/mL). Compound 68f with bromine at C-6 showed better activity against M. litoralis (MIC = 6.25 μg/mL), whereas 68a with methyl at C-6 showed better activity against S. aureus (MIC = 12.5 μg/mL). No compound has good activity against B. subtilis with the standard drug streptomycin, respectively. DPPH (1,1-diphenyl-2-picryl-hydrazil) radical scavenging method has been chosen to evaluate the antioxidant potential of the compounds 68a–g compared with that of commercial antioxidant butylated hydroxytoluene (BHT). The results in percentage are expressed as of absorbance decrease at 517 nm, and the absorbance of DPPH solution in the absence of compounds. The values revealed that the radical scavenging activity of 7-(2-chloroquinolin-4-yloxy)-4-methyl-2H-hromen-2-one on DPPH radicals increases with the increase in concentration. Compounds possessing chloro, bromo substituents at C-6 (68e,f), showed maximum activity at a concentration of 1000 μg/mL. The radical scavenging activity of compounds possessing methyl at C-7 (68b) exhibited less potent than the standard. In summary, these compounds have been subjected to antimicrobial screening against a panel of human pathogens, and most of them are found to be more active than the standard drugs. In addition, antioxidant activity for compound 68e shows a moderate 78% of inhibition. The binding energy value of synthesized compounds is less than the standard antimalarial drugs like chloroquine and amodiaquine.

Khatkar and colleagues [57] synthesized a quinoline ferulic acid derivative 69 (Figure 14) (Table 9). The synthesized compound was evaluated in vitro for its antibacterial activity against various Gram-positive and Gram-negative bacterial and fungal strains. As a result, compound 69 was found to be most effective against B. subtilis with a pMICbs value of 2.01.

Figure 14. The chemical structures of antibacterial compounds 67–69.

Maddela and colleagues [58] designed and synthesized the isatin–quinoline derivative compound 70 (Figure 15) (Table 9) and evaluated its antitubercular activity against Mycobacterium tuberculosis. Compound 70 had a MIC of 0.09 mg/L and showed good inhibitory activity compared to the standard drug isoniazid.

Tabbi and colleagues [59] synthesized new adamantane-containing chalcones derivatives 71–73 (Figure 15) (Table 9) and evaluated their resistance against Enterococcus faecalis 29212, Pseudomonas aeruginosa ATCC 27853, strong antibacterial activity against Escherichia coli and interesting antifungal activity against Candida albicans ATCC 90030. Compounds 71–73 were also tested for anti-Candida activity. All compounds were found to have the same activity as ketoconazole against C. glabrata ATCC 90030 (MIC = 200 μg/mL). However, the compounds had no significant anti-Candida activity against C. krusei ATCC 6258 (MIC = 100 μg/mL).

Pan and colleagues [60] synthesized hydroxycoumarin quinoline derivatives 74a–b (Figure 15) (Table 9) to evaluate their antifungal activity. Compound 74b exhibited potent growth inhibition against all tested fungi. (The inhibition rates of compound 74b against A. alternate, A. solani, B. cinerea, and F.oxysporum were 57.6%, 79.0%, 72.9%, and 89.6%, respectively). Compound 74a exhibited moderate activity. The inhibition rates of compound 74a against A. alternate, A. solani, B. cinerea, and F. oxysporum were 49.3%, 61.2%, 63.3%, and 56.4%, respectively. In contrast, compound 74b exhibited selective antifungal activity against A. alternata and A. solani, which were alternatively present.

Naphthoquinone (CF: C₁₀H₆O₂, MW: 158.15, Naphthalene-1,4-dione) is an organic substance, and theoretically, there are 6 kinds of naphthoquinone, of which only 1,4-, 1,2-, and 2,6- can be obtained stably. 1,4-Naphthoquinone, also known as α-naphthoquinone, is used to make dyes, medicines, and fungicides. Kalt and colleagues [61] synthesized 1,4-naphthoquinonequinoline derivative 75 (Figure 15) (Table 9) and tested its anti-mycobacterial activity. The results showed that compound 75 had a slight inhibitory effect against mycobacteria with a MIC of 8 μg/mL.

Lasiokaurin (molecular formula: C₂₂H₃₀O₇, MW: 406.47, (1α,6β,7α,14R)-1-(Acetyloxy)-7,20-epoxy-6,7,14-trihydroxykaur-16-en-15-one) is a diterpene compound present in the leaves of the Lamiaceae plant, Isodon trichocarpus Kudo, and the leaves of Rabdosia japonica (Burm.f.) Hara. Li and colleagues [62] synthesized quinoline-based lasiokaurin derivative 76 (Figure 15) (Table 9) and performed antibacterial tests. The results showed that compound 76 exhibited the most promising antibacterial activity with MICs of 2.0 and 1.0 μg/mL against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis, respectively.

Figure 15. The chemical structures of antibacterial compound 70–76.

Table 9. Quinoline derivatives with antibacterial activity.

Compd.	Activity	Origin	Ref
56a	E. coli MIC = 25.0 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
56b	E. coli MIC = 12.5 μg/mL S. aureus MIC = 25.0 μg/mL C. albicans MIC = 25.0 μg/mL	synthetic	[48]
56c	E. coli MIC = 6.25 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
56d	E. coli MIC = 12.5 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 25.0 μg/mL	synthetic	[48]
56e	E. coli MIC = 6.25 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
56f	E. coli MIC = 12.5 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
56g	E. coli MIC = 12.5 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
56h	E. coli MIC = 12.5 μg/mL S. aureus MIC = 25.0 μg/mL C. albicans MIC = 25.0 μg/mL	synthetic	[48]
57a	E. coli MIC = 12.5 μg/mL S. aureus MIC = 12.5 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
57b	E. coli MIC = 12.5 μg/mL S. aureus MIC = 25.0 μg/mL C. albicans MIC = 12.5 μg/mL	synthetic	[48]
58a	B.s. MIC = 500 μg/mL S.a. MIC = 250 μg/mL E.c. MIC = 100 μg/mL S.t. MIC = 100 μg/mL A.n. MIC = 500 μg/mL C.a. MIC = 500 μg/mL	synthetic	[49]
58b	B.s. MIC = 250 μg/mL S.a. MIC = 200 μg/mL E.c. MIC = 500 μg/mL S.t. MIC = 250 μg/mL A.n. MIC = 200 μg/mL C.a. MIC = 500 μg/mL	synthetic	[49]
58c	B.s. MIC = 200 μg/mL S.a. MIC = 250 μg/mL E.c. MIC = 62.5 μg/mL S.t. MIC = 100 μg/mL A.n. MIC = 250 μg/mL C.a. MIC = 250 μg/mL	synthetic	[49]
58d	B.s. MIC = 250 μg/mL S.a. MIC = 125 μg/mL E.c. MIC = 62.5 μg/mL S.t. MIC = 100 μg/mL A.n. MIC = 500 μg/mL C.a. MIC = 1000 μg/mL	synthetic	[49]
58e	B.s. MIC = 250 μg/mL S.a. MIC = 125 μg/mL E.c. MIC = 200 μg/mL S.t. MIC = 250 μg/mL A.n. MIC = 500 μg/mL C.a. MIC = 1000 μg/mL	synthetic	[49]
58f	B.s. MIC = 250 μg/mL S.a. MIC = 500 μg/mL E.c. MIC = 100 μg/mL S.t. MIC = 62.5 μg/mL A.n. MIC = 1000 μg/mL C.a. MIC = 250 μg/mL	synthetic	[49]
58g	B.s. MIC = 250 μg/mL S.a. MIC = 200 μg/mL E.c. MIC = 100 μg/mL S.t. MIC = 200 μg/mL A.n. MIC = 1000 μg/mL C.a. MIC = 200 μg/mL	synthetic	[49]
58h	B.s. MIC = 200 μg/mL S.a. MIC = 250 μg/mL E.c. MIC = 100 μg/mL S.t. MIC = 200 μg/mL A.n. MIC = 500 μg/mL C.a. MIC = 250 μg/mL	synthetic	[49]
58i	B.s. MIC = 500 μg/mL S.a. MIC = 250 μg/mL E.c. MIC = 250 μg/mL S.t. MIC = 250 μg/mL A.n. MIC = 1000 μg/mL C.a. MIC = 200 μg/mL	synthetic	[49]
58j	B.s. MIC = 500 μg/mL S.a. MIC = 100 μg/mL E.c. MIC = 62.5 μg/mL S.t. MIC = 100 μg/mL A.n. MIC = 1000 μg/mL C.a. MIC > 1000 μg/mL	synthetic	[49]
58k	B.s. MIC = 200 μg/mL S.a. MIC = 125 μg/mL E.c. MIC = 100 μg/mL S.t. MIC = 200 μg/mL A.n. MIC = 1000 μg/mL C.a. MIC = 1000 μg/mL	synthetic	[49]
58l	B.s. MIC = 250 μg/mL S.a. MIC = 100 μg/mL E.c. MIC = 200 μg/mL S.t. MIC = 250 μg/mL A.n. MIC > 1000 μg/mL C.a. MIC = 1000 μg/mL	synthetic	[49]
59a	MTB MIC₅₀ = 8.7 μg/mL MIC₉₀ = 25.5 μg/mL M. Bovis BCG MIC₅₀ = 12.9 μg/mL MIC₉₀ > 30 μg/mL	synthetic	[50]
59b	MTB MIC₅₀ > 30 μg/mL MIC₉₀ > 30 μg/mL M. Bovis BCG MIC₅₀ = 2.5 μg/mL MIC₉₀ > 30 μg/mL	synthetic	[50]
59c	MTB MIC₅₀ = 2.8 μg/mL MIC₉₀ > 30 μg/mL M. Bovis BCG MIC₅₀ = 1.4 μg/mL MIC₉₀ = 2.7 μg/mL	synthetic	[50]
59d	MTB MIC₅₀ = 27.8 μg/mL MIC₉₀ > 30 μg/mL M. Bovis BCG MIC₅₀ = 19.7 μg/mL MIC₉₀ > 30 μg/mL	synthetic	[50]
60a	MTB MIC₅₀ = 6.7 μg/mL MIC₉₀ = 26.5 μg/mL M. Bovis BCG MIC₅₀ = 6.0 μg/mL MIC₉₀ = 7.3 μg/mL	synthetic	[50]
60b	MTB MIC₅₀ = 7.7 μg/mL MIC₉₀ = 20.0 μg/mL M. Bovis BCG MIC₅₀ = 5.8 μg/mL MIC₉₀ = 15.4 μg/mL	synthetic	[50]
60c	MTB MIC₅₀ = 2.3 μg/mL MIC₉₀ = 7.8 μg/mL M. Bovis BCG MIC₅₀ = 5.8 μg/mL MIC₉₀ = 9.4 μg/mL	synthetic	[50]
60d	MTB MIC₅₀ > 30 μg/mL MIC₉₀ > 30 μg/mL M. Bovis BCG MIC₅₀ = 3.3 μg/mL MIC₉₀ = 21.5 μg/mL	synthetic	[50]
61	MDR MIC₉₉ = 0.649 μM XDR-TB MIC₉₉ = 0.736 μM	synthetic	[51]
62a	B. subtilis MIC = 0.020 mg/mL S. aureus MIC = 1.25 mg/mL M. smegmatis MIC = 0.625 mg/mL F. oxysporum MIC = 0.625 mg/mL	synthetic	[52]
62b	B. subtilis MIC = 1.25 mg/mL S. aureus MIC = 2.5 mg/mL	synthetic	[52]
62c	B. subtilis MIC = 1.25 mg/mL S. aureus MIC = 1.25 mg/mL K. pneumoniae MIC = 0.625 mg/mL	synthetic	[52]
62d	B. subtilis MIC = 1.25 mg/mL S. aureus MIC = 1.25 mg/mL M. smegmatis MIC = 0.625 mg/mL	synthetic	[52]
62e	B. subtilis MIC = 1.25 mg/mL S. aureus MIC = 1.25 mg/mL M. smegmatis MIC = 0.625 mg/mL C. albicans MIC = 0.156 mg/mL Klebsiella pneumoniae MIC = 0.625 mg/mL	synthetic	[52]
62f	B. subtilis MIC = 1.25 mg/mL S. aureus MIC = 1.25 mg/mL M. smegmatis MIC = 0.625 mg/mL	synthetic	[52]
63	inhibited EtBr efflux > 65% at 50 μM	synthetic	[53]
64	inhibited EtBr efflux > 65% at 50 μM	synthetic	[53]
65	Sclerotinia sclerotiorum EC₅₀ = 1.57 mg/L	synthetic	[54]
66	V. mali EC₅₀ = 1.56 mg/L B. cinerea EC₅₀ = 1.54 mg/L	synthetic	[54]
67a	-	synthetic	[55]
67b	-	synthetic	[55]
67c	Pseudomonas aeruginosa MIC = 18 μg/mL	synthetic	[55]
67d	-	synthetic	[55]
67e	Staphylococcus aureus MIC = 21 μg/mL Bacillus subtilis MIC = 19 μg/mL	synthetic	[55]
67f	Pseudomonas aeruginosa MIC = 19 μg/mL	synthetic	[55]
67g	Staphylococcus aureus MIC = 28 μg/mL Bacillus subtilis MIC = 26 μg/mL	synthetic	[55]
67h	Staphylococcus aureus MIC = 40 μg/mL Bacillus subtilis MIC = 24 μg/mL	synthetic	[55]
67i	-	synthetic	[55]
67j	StaphylococcusAureus MIC = 24 μg/mL Bacillus subtilis MIC = 40 μg/mL	synthetic	[55]
68a	Escherichia coli MIC = 12.5 μg/mL Pseudomonas aeruginosa MIC = 100 μg/mL Staphylococcus aureus MIC = 12.5 μg/mL	synthetic	[56]
68b	Pseudomonas aeruginosa MIC = 12.5 μg/mL	synthetic	[56]
68c	Escherichia coli MIC = 6.25 μg/mL Meloidogyne litoralis MIC = 100 μg/mL	synthetic	[56]
68d	Escherichia coli MIC = 6.25 μg/mL Pseudomonas aeruginosa MIC = 6.25 μg/mL Bacillus subtilis MIC = 100 μg/mL	synthetic	[56]
68e	Escherichia coli MIC = 100 μg/mL Pseudomonas aeruginosa MIC = 12.5 μg/mL Meloidogyne litoralis MIC = 100 μg/mL Staphylococcus aureus MIC = 50 μg/mL	synthetic	[56]
68f	Pseudomonas aeruginosa MIC = 50 μg/mL Meloidogyne litoralis MIC = 6.25 μg/mL	synthetic	[56]
68g	Escherichia coli MIC = 6.25 μg/mL Pseudomonas aeruginosa MIC = 6.25 μg/mL Staphylococcus aureus MIC = 50 μg/mL	synthetic	[56]
69	B. subtilis pMICbs = 2.01	synthetic	[57]
70	Mycobacterium tuberculosis MIC = 0.09 mg/L	synthetic	[58]
71a	C. glabrata ATCC 90030 MIC = 200 μg/mL	synthetic	[59]
71b	C. glabrata ATCC 90030 MIC = 200 μg/mL	synthetic	[59]
72	C. glabrata ATCC 90030 MIC = 200 μg/mL	synthetic	[59]
73	C. glabrata ATCC 90030 MIC = 200 μg/mL	synthetic	[59]
74a	A. alternate inhibition rate = 49.3% A. solani inhibition rate = 61.2% B. cinerea inhibition rate = 63.3% F. oxysporum inhibition rate = 56.4%	synthetic	[60]
74b	A. alternate inhibition rate = 57.6% A. solani inhibition rate = 79.0% B. cinerea inhibition rate = 72.9% F. oxysporum inhibition rate = 89.6%	synthetic	[60]
75	Mycobacteria MIC = 8 μg/mL	synthetic	[61]
76	Staphylococcus aureus MIC = 2.0 μg/mL Bacillus subtilis MIC = 1.0 μg/mL	synthetic	[62]

Summary: Quinoline-based molecules have been found to be very effective in inhibiting microbial pathogens. Among the drugs of quinoline scaffolds, fluoroquinolone antibiotics, represented by ciprofloxacin, are a large class of antibiotics. In addition, bedaquiline is a diarylquinoline-based drug that has been used to treat multidrug-resistant tuberculosis (MDR-TB). In order to adapt to environmental changes, especially the use of antibiotics, bacteria have developed a variety of mechanisms to resist various adverse conditions. Therefore, bacterial infection has once again evolved into a serious threat worldwide. The increasing number of multidrug-resistant microbial strains and new advances in untreatable infections make the treatment of bacterial infections difficult.

Compound 62e showed excellent antitubercular activity with MIC value 0.156 µg/mL against dormant C. albicans strain. Compound 70 against Mycobacterium tuberculosis showed the strongest inhibitory activity with a MIC value of 0.09 μg/mL. Compound 76 exhibited the most promising antibacterial activity with MICs of 2.0 and 1.0 μg/mL against the Gram-positive Bacteria Staphylococcus aureus and Bacillus subtilis, respectively.

These results suggest that the introduction of quinoline on the basis of aurone, isatin, and lasiokaurin can enhance antibacterial activity. However, there is no obvious rule between the introduced sites and the substituents on quinoline; moreover, the antibacterial mechanism of these compounds has not been studied.

3.10. Anticancer Activity

Lombard and colleagues [39] synthesized two quinoline–coumarin derivatives 43–44 (Figure 11) (Table 10) and evaluated their anticancer activity against kidney cancer (TK10), melanoma (UACC62), and breast cancer (MCF7) cell lines, etoposide was used as a positive control. The results of the five-dose cancer screening showed that mixed dimer 44 was less active, and its anticancer activity was classified as against renal (TGI = 18.5 μM) and melanoma (TGI = 17.43 μM) cell linesmoderate. The breast (MCF7) cell line showed higher sensitivity to dimer 44 with a TGI of 2.92 μM, so the activity of dimer 44 could be classified as potent for this cell line. Dimer 44 was 2-fold (TGI, 18.5 vs. 43.33 μM), 15-fold (TGI, 2.92 vs. 43.52 μM), and 5.7-fold (TGI, 17.43 vs. >100 μM) activity than etoposide against TK10, UACC62, and MCF7, respectively. The synthetic dimer exhibited moderate to potent anticancer activity against the cell lines studied and inhibited the growth of all three cell lines at very low concentrations (GI₅₀ values in the range of 0.03–0.08 μM). Compound 43 was able to inhibit the growth of all three cell lines at 10 μM, while compound 44 could inhibit the growth of the UACC62 cell line and the other two cell lines at 100 μM only at 10 μM. Very low LC₅₀ and LC₁₀₀ values were obtained for both compounds; moreover, these two compounds have very low toxicity to normal cells.

Tabbi and colleagues [59] synthesized the adamantane chalcone–quinoline derivatives 71a–b (Figure 15) (Table 10) and evaluated their in vitro anticancer activity against human pancreatic cancer cells Mia Paka 2. The growth inhibitory activities of compounds 71a and 71b were 85% and 77%. Thus, compounds 71a–b possess some anticancer activity.

Abonia and colleagues [63] synthesized novel quinoline-2-ketochalcone derivative 77 (Figure 16) (Table 10). In vitro antitumor assays showed that compound 77 exhibited high activity in the samples selected and evaluated by NCI. In particular, compound 77 showed the most significant activity against 50 human tumor cell lines with GI₅₀ values of 1.0 μM, with HCT-116 (colon, GI₅₀ = 0.131 μM) and LOX IMVI (melanoma, GI₅₀ = 0.134 μM) being the most susceptible strains.

Podophyllotoxin (CF: C₂₂H₂₂O₈, MW: 414.41, 1,3,3a,4,9,9a-hexahydro-9-hydroxy-6,7-(methylenedioxy)-4-(3′,4′,5′-trimethoxyphenyl)benz[f]isobenzofuran-3-one), also known as podafilol, is a non-alkaloid lignin-like toxin. Kamal and colleagues [64] synthesized the onychotoxin–quinoline derivatives 78a–b and 79a–b (Figure 16) (Table 10) and evaluated their higher activity against A549, A375, MCF-7, HT-29, and ACHN, and the positive control drugs etoposide and doxorubicin than they themselves. The IC₅₀ values of compound 78a against A549, A375, MCF-7, HT-29, and ACHN were 15.4 μM, 14.5 μM, 13.8 μM, 12.3 μM, and 10.8 μM, respectively. The IC₅₀ values of compound 78b against A549, A375, MCF-7, HT-29, and ACHN were 13.4 μM, 7.7 μM, 11.2 μM, 7.75 μM, and 15.7 μM, respectively. The IC₅₀ values of compound 79a against A549, A375, MCF-7, HT-29, and ACHN were 10.6 μM, 10.3 μM, 8.6 μM, 11.8 μM, and 10.7 μM, respectively. The IC₅₀ values of compound 79b against A549, A375, MCF-7, HT-29, and ACHN were 7.7 μM, 6.8 μM, 2.2 μM, 8.9 μM, and 9.46 μM, respectively.

Ring-A 3,4-seco-cycloartane-type triterpenes (CF: C₃₀H₄₄O₂, MW: 468.67, (3R,3aR,5aS,6aR,6bR,9aR,10aS,10bS)-3-[(1R)-1,5-Dimethyl-4-hexen-1yl]tetradecahydro-3a) mainly exist in the gardenia plants of Rubi ceae. Pudhom and colleagues [65] synthesized 3,4-eco-cycloartane-type triterpene quinoline derivative 80 (Figure 16) (Table 10) and evaluated the effect on angiogenesis. The inhibition rate of compound 80 ranged between 50 and 60%.

Kamal and colleagues [66] synthesized 4b-sulfonamide and 4b-[(40-sulfonamide)benzamide] conjugates of podophyllotoxin 81 (Figure 16) (Table 10) and evaluated its effect on anticancer activity. The results showed that the inhibition A549 activity of compound 81 was more potent than that of the positive control drugs doxorubicin and etoposide (the GI₅₀ of compound 81 was 2.51 μM).

Zhao and colleagues [67] synthesized 4′-demethylghostatin (DMEP) quinoline derivatives 82–83 (Figure 16) (Table 10) and evaluated their anticancer activity. The inhibitory activity of compound 82 on HepG2, HeLa, A549, and BGC-823 was stronger than that of itself and the positive control etoposide. The IC₅₀ values of compound 82 against HepG2, HeLa, A549, BGC-823, and HL-7702 were 16.03 μM, 0.60 μM, 10.05 μM, 17.41 μM, and 41.77 μM, respectively. The inhibitory activity of compound 83 on HepG2 and A549 is stronger than that of itself and the positive control. The inhibitory activity of compound 83 on HeLa and BGC-823 is not as good as its own. The IC₅₀ values of compound 90 against HepG2, HeLa, A549, BGC-823, and HL-7702 were 9.18 μM, 20.53 μM, 19.20 μM, 28.81 μM, and 20.09 μM, respectively. Compounds 82–83 are both on HL-7702 was more toxic than itself.

Ayan and colleagues [68] synthesized a derivative of the aminosteroidal E-37P-quinoline derivative 84 (Figure 16) (Table 10) and evaluated their anticancer activity. The results showed that compound 84, a 5a-androstane-3a,17b-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2b and an ethinyl at position 17a, showed very good antiproliferative activity among the five cancer cell lines studied. The IC₅₀ values of compound 84 for HL-60, MCF-7, T-47D, LNCaP, and WEHI-3 were 0.1, 0.1, 0.1, 2.0, and 1.1 μM, respectively. Furthermore, compound 84 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a low risk of drug-drug interactions.

Cui and colleagues [69] synthesized quinoline-like estrone-17-hydrazone 85 (Figure 16) (Table 10) and assayed its activities against the proliferation of HeLa, HT-29, Bel 7404, and SGC 7901, respectively. The results showed that compound 85 had a quinoline structure on the side chain of 17 and showed a better effect. The antiproliferative activity against test cells in vitro was higher than that of the positive control drug cisplatin. In particular, compound 85 showed excellent antiproliferative activity against SGC 7901 in vitro with an IC₅₀ value of 1 μM.

Berberine (CF: C₂₀H₁₈NO₄⁺, MW: 336.36, 16,17-dimethoxy-5,7-dioxa-13-azoniapentacyclo [11.8.0.0^2,10.0^4,8.0^15,20] henicosa-1(13),2,4(8),9,14,16,18,20-octaene), a quaternary alkaloid isolated from the traditional Chinese medicine Coptis chinensis, is the main active ingredient in the antibacterial activity of Coptis. Jin and colleagues [70] synthesized quinoline berberine derivative 86 (Figure 16) (Table 10) and determined its antiproliferative activity against MCF-7, MCF-7/ADR, SW-1990 and SMMC-7721, and non-cancerous HUVEC cells. The results showed that the antiproliferative activity of compound 86 against four human cancer cell lines was slightly weaker (The IC₅₀ values of compound 86 for MCF-7, MCF-7/ADR, SW1990, and SMMC-7721 were 181.478 μM, 96.523 μM, 111.837 μM, and 75.546 μM, respectively), only inhibited MCF-7 and SMMC-7721 better than itself.

Hayat and colleagues [71] synthesized 4-azanonaphtholide quinoline derivative 87 (Figure 16) (Table 10) and evaluated its antiproliferative activity against five representative cancer cell lines HepG2, A431, A549, MCF 7, and HCT 116. Daurinol served as a positive control. Compound 87 showed almost equivalent activity to daurinol at 10 μM. The IC₅₀ values of compound 87 for HepG2, A431, A549, MCF 7, and HCT 116 were 8.40 μM, 11.56 μM, 4.33 μM, 5.99 μM, and 3.48 μM, respectively, exhibited a slightly stronger activity.

Srivastava and colleagues [72] synthesized quinoline–stilbene derivative 88 (Figure 16) (Table 10) and studied it for antiproliferative activity. Compound 88 showed surprisingly strong activity against MDA-MB 468 breast cancer cells (IC₅₀ = 0.12 μM).

Figure 16. The chemical structures of anticancer compounds 77–88.

Raghavan and colleagues [73] synthesized curcumin–quinolone derivative 89 (Figure 17) and performed in vitro cytotoxicity assays against A549, MCF7, SKOV3, and H460. Compound 115 showed the greatest activity against SKOV3 cells with a minimum IC₅₀ value of 12.8 μM observed and was therefore used for further biological experiments. At the IC₅₀ concentration, the compound was not toxic to the normal fibroblast cell line NIH3T3, with a cell survival rate of 74.5%.

Cui and colleagues [74] synthesized a steroidal quinoline derivative 90 (Figure 17) (Table 10) with a cholestane type 17-branched structure and determined its inhibitory effect in human hepatoma cells (Bel-7404) and gastric cancer cells (SGC-7901). Compound 90 showed significant growth and proliferation inhibition in both tumor cells, and both were stronger than the positive control cisplatin (IC₅₀ values of 90 were 28.7, 17.9 µmol/L).

He and colleagues [75] synthesized quinoline pregnenolone derivative 91 (Figure 17) (Table 10) and the inhibitory activity against human colon cancer cells (HT-29), human cervical cancer cells (HeLa) and human gastric cancer cells (SGC-7901), using cisplatin as a positive control, showed that compound 91 was superior to the inhibitory activity of the positive control substance cisplatin; the inhibitory activity against HeLa and SGC-7901 cells was less than 10 μmol/L (compound 91’s IC₅₀ values were 14.1, 9.1, 8.2 μmol/L).

Baji and colleagues [76] synthesized novel D- and A-ring-fused quinolines of the estrone and 5α-androstanes series 92–95 (Figure 17) (Table 10) and investigated their antiproliferative activity on human cervical cancer (C33A, HeLa, and SiHA) and breast cancer (MCF-7, MDA-MB-231, MDA-MB-361, and T47D) cell lines. The results indicated that ring D-fused quinolines 92a–c exhibited weak or modest antiproliferative properties, typically eliciting 30–50% growth inhibition at 30 µM. The cytostatic activities of benz[c]acridine derivatives 93a–f were even weaker, except for 93e and 93f, which blocked the proliferation of HeLa cells selectively with IC₅₀ values comparable to that of the reference agent cisplatin. IC₅₀ values of 93e–f were 99.6 and 89.4 µM, respectively. Ring A-fused quinolines generally inhibited cellular growth more efficiently. Compounds with a 17-OH group (95a–c and 95e–g) tended to display more pronounced action than the corresponding 17-OAc analogues (94a–c and 94e–g). Since the efficacy of analogue 95a containing an unsubstituted quinoline moiety was similar to those of 95b–h, the character of the substituent on the quinoline does not seem to be crucial for the antiproliferative actions; however, substitution at position 6′ (95c, 95e, and 95f) appeared favorable. The efficacy of 95c against T47D cells was comparable to that of the reference agent cisplatin. IC₅₀ value of 95c was 80.4 µM.

Combretastatin A-4 (CA-4, CF: C₁₈H₂₀O₅, MW: 316.3484, (Z)-2-Methoxy-5-(3,4,5-trimethoxystyrene)phenol) is a novel vasopressor that targets tubulin in vivo, inhibiting its polymerization and further selectively destroying the vascular endothelium of tumor tissues, closing the vasculature of tumor tissues and rendering them hypoxic and nutritious, thus acting as an antitumor agent. Chaudhary and colleagues [77] synthesized combretastatin A-4 quinoline derivative 96 (Figure 17) (Table 10) and evaluated its antiproliferative activity. The results showed that compound 96 had higher antiproliferative activity than CA-4. In addition, compound 96 inhibited the migration of highly metastatic MDA-MB-231 more strongly than CA-4, indicating its potent anti-metastatic potential. Compound 96 inhibited the rate and extent of in vitro assembly of purified tubulin with an IC₅₀ of 1.6 μM and a dissociation constant of 1.9 μM.

Maslinic acid (CF: C₃₀H₄₈O₄, MW: 472.71, (2α,3β)-2,3-dihydroxyolean-12-en-28-acid) is a pentacyclic triterpene acid, found in hawthorn, red dates, loquat leaves, and olive oil. Madecassic acid (CF: C₃₀H₄₈O₆, MW: 504.70, (2α,3β,4α,6β)-2,3,6,23-Tetrahydroxyurs-12-en-28-oic acid) is derived from the whole grass of Centella Asiatica of the Umbelliferae. Sommerwerk and colleagues [78] synthesized maslinic acid derivative quinoline derivative 97a–l (Figure 17) (Table 10) and madecassic acid quinoline derivative 98 and evaluated their antitumor activity. Although the cytotoxicity of compounds 97a–d and 97g–j was similar to that of pyridyl-substituted amides, the 8-quinolinyl derivatives 97k and 97l exhibited selective cytotoxicity against different human tumor cell lines; however, their overall cytotoxicity was low, and their solubility in water was poor. However, the 5-quinolinyl-substituted compounds 97e and 97f performed better, as their EC₅₀ values were quite low, and they were cytotoxic against human tumor cell lines but significantly less cytotoxic against non-malignant mouse fibroblasts. Compound 98 has an isoquinoline group present, which shows both low EC₅₀ values (EC₅₀ = 80 μM for A2780) and high tumor/non-malignant cell selectivity (EC₅₀ = 3.23 μM for NIH 3T3, resulting in a selectivity index of 40).

Figure 17. The chemical structures of anticancer compounds 89–98.

Shobeiri and colleagues [79] synthesized 2-aryl-trimethoxyquinoline derivatives 99a–e (Figure 18) (Table 10) and evaluated the cytotoxic activity of the synthesized compounds against four human cancer cell lines MCF-7, MCF-7/MX, A-2780, and A-2780/RCIS. The results showed that all the alcohol derivatives 99a–e showed greater cytotoxicity against the A-2780 cell line compared to the other three cell lines IC₅₀ ranging from 7.98 to 60 μM. Interestingly, drug-resistant human breast cancer cells (MCF-7/MX) were more sensitive to all alcohol derivatives except 99a than the parental cells (MCF-7). In contrast, they induced more cytotoxicity in the A-2780 cell line compared to resistant human ovarian cancer (A-2780/RCIS), suggesting that compounds may exert their cytotoxic activity in different tumor cell types through different mechanisms. Among these quinolines, compound 99e, which possesses a trimethoxyphenyl group at the second position of the quinoline ring, exhibited the strongest cytotoxicity against cancer cell lines, with the same effect on both parental and resistant cell lines.

Zhang and colleagues [80] synthesized the podophyllotoxin quinoline derivatives 100–102 (Figure 18) (Table 10) and evaluated their antiproliferative activity against human leukemia cells (K562 and K562/ADR). Etoposide and doxorubicin were used as positive compounds. Compounds 100–102 showed potent cytotoxicity comparable to or higher than etoposide and doxorubicin (IC₅₀ values for the antiproliferative activity of compound 100 were 0.061 and 0.064 μM for K562 and K562/ADR cells, respectively. Compound 101 for K562 and K562/ADR cells. IC₅₀ values of 0.177 and 0.064 μM for antiproliferative activity and 0.034 and 0.022 μM for compound 102 on K562 and K562/ADR cells, respectively. In general, the activity of the tested molecules was higher against K562 cells than against K562/ADR cells. Moreover, the IC₅₀ value of compound 102 in K562/ADR cells was 0.034 μM; its activity was 65.029 and 552.323 times higher than that of etoposide and doxorubicin, respectively.

Li and colleagues [81] synthesized a podophyllotoxin-derived quinoline derivative 103 (Figure 18) (Table 10) and evaluated its antiproliferative activity against human promyelocytic leukemia cells HL60, human gastric cancer cells SGC-7901, human colon cancer cells MCF-7, human in vitro anticancer active breast cancer cells HCT116, and human non-small cell lung cancer cells A549. Unfortunately, the anticancer activity of compound 103 was inferior to that of the positive control drug etoposide (IC₅₀ values arranged 8.09–73.40 μM).

Figure 18. The chemical structures of anticancer compounds 99–103.

Li and colleagues [62] synthesized a lasiokaurin quinoline derivative 104 (Figure 19) (Table 10) and evaluated the antiproliferative activity against human leukemia K562 cells, human gastric cancer MGC-803 cells, human esophageal cancer CaEs-17 cells, and human hepatocellular carcinoma Bel-7402 cells. The results showed that compound 104 inhibited Bel-7402 more strongly than the positive control drug paclitaxel (IC₅₀ values for compound 104 were 1.89, 1.03, 1.74, and 0.96 μM, respectively).

Ursolic acid (CF: C₃₀H₄₈O₃, MW: 456.700, (3β)-3-Hydroxyurs-12-en-28-oic acid) is a natural triterpenoid carboxylic acid compound present in the Labiatae plant Prunella vulgaris L. Gu and colleagues [82] synthesized a series of novel ursolic acid quinoline derivatives 105–107 (Figure 19) (Table 10) and evaluated their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela, and SMMC-7721). From the results, compounds 105a–d exhibited significant antitumor activity against three cancer cell lines. Compounds 105a–d, 106i, and 111c showed prominent cytotoxic activities against at least one cancer cell line (IC₅₀ < 10 μM). Among them, compound 105b exhibited the most potent cytotoxic activity against MDA-MB-231, HeLa, and SMMC-7721 cells with IC₅₀ values of 0.61 ± 0.07, 0.36 ± 0.05, and 12.49 ± 0.08 μM, respectively, stronger than those of positive control. Compound 105a also showed anticancer activity against the three cancer cells slightly weaker than compound 105b. However, compound 105a had a stronger anticancer activity than that of all other compounds. Compounds 105a–d, 106i, and 107c did not show considerable cytotoxicity against normal hepatocyte cells QSG-7701 with IC₅₀ > 40 μM. In addition, compounds 106a, 106c, 106d, 106f, 106g, 106l, 107a, 107d, 107f, 107i, and 107l showed moderate inhibition to three cancer cell lines. Compounds 106b, 106e, 106h, 106k, 107b, 107e, and 107k showed weak inhibitory activities against HeLa cells and were not cytotoxic to MDA-MB-231 and SMMC-7721 cells (IC₅₀ > 40 μM), while compound 111h was inactive to all tested cancer cells. Especially, compound 105b was found to be the most potent derivative with IC₅₀ values of 0.61, 0.36, and 12.49 μM against MDA-MB-231, HeLa, and SMMC-7721 cells, respectively, stronger than positive control etoposide.

Gan and colleagues [83] synthesized steroidal quinoline derivatives 108–109 (Figure 19) (Table 10) and evaluated their in vitro effects on human HeLa, HT-29, Bel 7404, and antiproliferative activity in SGC 7901 cells. The anticancer activities of compound 108 and cisplatin were comparable (IC₅₀ values of 11.2, 21.3, 28.9, and 10.3 μM/L), while the anticancer activity of compound 109 was inferior to that of cisplatin.

Yao and colleagues [84] synthesized the dihydroartemisinin quinoline hydrazone derivative 110 (Figure 19) (Table 10). Using 5-fluorouracil or paclitaxel as positive controls, the results showed that compound 110 showed more pronounced antitumor activity against MCF-7 cells than that of the positive group. In addition, 110 showed low cytotoxicity against normal human cells.

Figure 19. The chemical structures of anticancer compounds 104–110.

Aly and colleagues [85] synthesized a new set of fused naphtho[3,2-c]quinoline-6,7,12-trione and naphtho[3,2-c]quinoline-6,7,8,13-tetrone compounds 111 and 112 (Figure 20) (Table 10) for in vitro anticancer screening. The results showed that compounds 111 and 112 had good potency against ERK, which makes it important to investigate the possible application of these inhibitors in RAF-mutant melanoma (IC₅₀ of compounds 111 and 112 were 0.6 and 0.16 μM).

Sri and colleagues [86] synthesized a curcumin-receptor 2-chloro/phenoxy quinoline derivative 113 (Figure 20) (Table 10) and tested their antitumor activity against several cancer cell lines, such as HeLa, HGC-27, NCI-H460, DU-145, PC-3, and 4T1. The IC₅₀ ranged from 1.81 to 12.4 μM. The IC₅₀ of compound 113 against PC-3, DU-145, NCI-H460, and 4 T1 were 3.12, 3.99, 3.96, and 1.81 μM, respectively.

Taheri and colleagues [87] synthesized coumarin–quinoline derivatives 114a–b (Figure 20) (Table 10) and determined their cytotoxic effects on A2780 human cancer cells using doxorubicin as a positive control. The results showed that the cytotoxicity of compounds 114a–b was significantly higher than that of the other derivatives, with IC₅₀ values of 25 and 62 μg/mL, respectively. Further examination revealed that compound 114a increased ROS levels, decreased MMPs, and induced apoptosis in A2780 cells via the intrinsic mitochondrial pathway; thus, compound 114a may be an appropriate agent for treating ovarian cancer.

Lipeeva and colleagues [88] synthesized amino coumarin–quinoline derivatives 115–116 (Figure 20) (Table 10) and evaluated their antiproliferative effects on leukemia CEM-13, MT-4, U-937, and melanoma MEL-8 cancer cells. Although compound 115 was more cytotoxic to cancer cells than the positive parent compound, they were lower than the positive control drug doxorubicin (IC₅₀ values arrange 30.5–47.3 μM). In contrast, the cytotoxicity of compound 116 on MCF-7 cells was comparable to that of the positive control drug doxorubicin. The GI₅₀ value of compound 116 was 10.5 μM.

Oridonin (CF: C₂₀H₂₈O₆, MW: 364.43, is a biologically active kaurine-type tetracyclic diterpene isolated from the genus plants Rabdosia in the family Lamiaceae (Iabtea). Shen and colleagues [89] synthesized oridonin derivatives 117–118 (Figure 20) (Table 10) and evaluated their antitumor activity in vitro against three human cancer cell lines, HCT116, BEL7402, and MCF7. Compared with the lead compound and the positive control drug 5-fluorouracil (5-Fu), compounds 117 and 118 exhibited potent antiproliferative efficacy against HCT116, MCF-7, and BEL7402 cancer cell lines. IC₅₀ values of 2.51, 0.41, and 2.54 μM, and IC₅₀ values for compound 118 were 2.07, 0.89, and 2.30 μM, respectively.

Zhao and colleagues [90] synthesized podophyllotoxin quinoline derivatives 119–122 (Figure 20) (Table 10) and evaluated them for antitumor activity assays against the following four human tumor cell lines: hepatocellular carcinoma cells HepG2, cervical cancer cells HeLa, lung cancer cells A549, and breast cancer cells MCF7. Clinical microtubule polymerization inhibitor nocodazole (Ncz), podophyllotoxin clinical drug etoposide (VP-16), PTOX, and DMEP were used as positive controls. The results showed that most of the anticancer activities of compounds 119–122 were inferior to the positive control. IC₅₀ values arranged 0.8–39.2 μM.

Prashanth and colleagues [91] synthesized coumarin quinoline derivative 123a–d (Figure 20) (Table 10) and evaluated its cytotoxicity in vitro against ascites EAC and Dalton’s lymphoma ascites DLA cells. The results showed that compounds 123a–d had low antitumor activity.

Figure 20. The chemical structures of anticancer compounds 111–123.

Jin and colleagues [92] synthesized ursolic acid quinoline derivatives 124–127 (Figure 21) (Table 10) and evaluated their in vitro antiproliferative activity against three cancer cell lines, MDA-MB-231, HeLa, and SMMC 7721; etoposide was used as a positive control. Regarding the different derivatives, compounds 124a–d with carboxyl groups exhibited potent cytotoxic activity against MDA-MB-231 and HeLa cells at low levels of 1 μM and moderate activity against SMMC-7721 cells. Among the acyl hydrazide derivatives 125a–h, compounds 125a–d also exhibited significant cytotoxic activity comparable to that of compounds 124a–d. Compounds 125e–h showed almost no activity against all three cancer cell lines (IC₅₀ > 50 μM). Regarding the oxadiazole derivatives 125a–h and thiadiazole derivatives 126a–h, compounds 125a and 125d exhibited potent cytotoxicity (IC₅₀ < 10 μM) against MDA-MB-231 and HeLa cells, respectively. Compounds 126b–c, 127a–b, and 127d showed moderate activity against MDA-MB-231 and HeLa cells, while compounds 126e–h, 127c, and 127e–h showed only slight or no cytotoxicity against the three cancer cell lines.

Figure 21. The chemical structures of anticancer compounds 124–127.

Yang and colleagues [93] synthesized steroidal quinoline derivatives 128a–l (Figure 22) (Table 10) and evaluated their in vitro antiproliferative activity against three human lung cancer cells, A549, A431, and H1975. Compounds 128a mildly inhibited the growth of A549, A431, and H1975 with IC₅₀ values of 15.21, 17.45, and 20.76 μM, respectively. Compounds 162b–d with halogen atoms were found to have comparable activity to 128a, while compounds 128e–f showed better antiproliferative activity against the tested lung cancer cells. In particular, compound 128f showed the highest potency against A549, A431, and H1975 with IC₅₀ values of 5.34, 6.21, and 7.25 μM, respectively. Compounds 128g–h with alkyl groups showed reduced but moderate antiproliferative activity compared to 128f; moreover, nitro-containing compounds 128i–j also showed moderate inhibitory activity against the tested cancer cells. Apparently, compounds 128k–l containing methoxy and phenyl, respectively, showed weaker growth inhibition against the tested cancer cells.

Figure 22. The chemical structures of anticancer compounds 128.

Li and colleagues [94] synthesized chalcone–quinoline derivatives 129–130 (Figure 23) (Table 10) and evaluated their antiproliferative effects in vitro, and compared them with the reference compound CA-4. Human chronic myeloid leukemia cell K562 was used for the first time. The results showed that all the newly synthesized compounds exhibited good antiproliferative activities in the nanomolar range, except for compounds 129j–k and 129n–o, which have an indole moiety as the B ring. Among them, compounds 129b and 129d with 3-amino-4-methoxyphenyl or 3-hydroxy-4-methoxyphenyl moieties showed the most potent activities with IC₅₀ values of 0.011 and 0.009 μM, respectively, which were comparable to CA-4 (IC₅₀ = 0.011 μM) and approximately 6-fold stronger than the parent compound (IC₅₀ = 0.060 μM). The methyl substituent at the α-position of the unsaturated carbonyl increased activity (129a vs. 129b, 129c vs. 129d, and 129k vs. 129l), and in compounds 129i–o, except for compounds 129l and 129m, the activity of most compounds in this series (IC₅₀ > 1 μM) is lower than its phenyl counterpart whose unsaturated double bond is substituted at the C-5 position of the indole moiety. In addition, the methyl substituent at the N-1 position of indole (129m) exhibited approximately 5-fold increased activity compared to the unsubstituted counterpart 129l. All compounds 130a–d showed good activity except 130d, which has a lactam instead of a quinoline ring. The steric hindrance of the C-2 group of the quinoline moiety appears to have a key effect on the activity, as compounds with smaller substitutions, such as CH₃ (129d IC₅₀ = 0.009 μM), NHCH₃ (130a IC₅₀ = 0.018 μM), OCH₃ (130b IC₅₀ = 0.030 μM), and H (130c IC₅₀ = 0.015 μM), were more active than other compounds with larger groups. Interestingly, the CH₃-substituted compound 129d exhibits slightly stronger activity than the corresponding unsubstituted counterpart 130c, despite the greater steric hindrance of methyl groups than hydrogen. The biological functions of more cancer cell lines were further evaluated. Four additional cancer cell lines, including human hepatocellular carcinoma (HepG2), nasopharyngeal epidermoid carcinoma (KB), human colon carcinoma cells (HCT-8), and human breast cancer cells (MDA-MB-231), were selected for further evaluation. K562 cells were the most sensitive of the five cancer cell lines tested, and the most active compound, 129d, exhibited comparable activity to the reference compound CA-4, with IC₅₀ values ranging from 0.009 to 0.016 μM. Notably, the activity of 129d increased approximately 6-fold compared to the parent compound; therefore, 129d was selected for further biological studies. In addition, the selectivity ratio of 129d to normal human liver L-O2 cells was 65.8 times higher than that of CA-4, indicating that the toxicity of 129d may be lower than that of CA-4.

Parthenolide (CF: C₁₅H₂₀O₃, MW: 248.32, (1aR,4E,7aS,10aS,10bR)-2,3,6,7,7a,8,10a,10b-Octahydro-1a,5-dimethyl-8-methyleneoxireno[9,10]cyclodeca[1,2-b]furan-9(1aH)-one) is a natural sesquiterpene lactone product isolated from medicinal plants, such as Salvia miltiorrhiza and Salvia miltiorrhiza. Jia and colleagues [95] synthesized a parthenolide quinoline derivative 131 (Figure 23) (Table 10) and determined its cytotoxic activity in HCT116, U87-MG, HepG2, BGC823, and PC9. Both paclitaxel (paclitaxel) and PTL (1a) were used as positive controls. The IC₅₀ values for compound 131 were 3.31, 1.47, 3.66, 1.77, and 3.12 μM.

Betulinic acid (CF: C₃₀H₄₈O₃, MW: 456.70, (3β)-3-Hydroxylup-20(29)-en-28-oic acid) is a natural lupin-type pentacyclic triterpenoid present in the leaves of Cyperus rotundus, the bark of birch trees and date palm kernels extracted from them. Platanic acid (CF: C₂₉H₄₆O₄, MW: 458.67, (3β)-3-Hydroxy-20-oxo-30-norlupan-28-oic acid) is a pentacyclic triterpenoid isolated from the leaves of Syzygium claviflorum. Hoenke and colleagues [96] prepared betulinic acid quinoline derivatives 132 (Figure 23) (Table 10) and platanic acid quinoline derivatives 133 and screened them for cytotoxicity. Compound 132 was the most cytotoxic in this study and also had the highest tumor or non-tumor cell selectivity, especially for A375 melanoma (S = 91.2), A2780 ovarian cancer (S = 61.6), and hypopharyngeal carcinoma FaDu (S = 59.0) cells. Compound 132 was slightly less selective than 167 (selectivity S was 41.4, 4.0, 19.2, 37.0, and 34.4, respectively). A375 melanoma cells were used in order to facilitate the understanding of their cytotoxicity pattern. The results showed that compound 166 also increased the number of apoptotic cells; however, more cells were in advanced stages. Similar behavior was observed when cells were treated with 133 (8.6% apoptotic and 9.6% late-stage apoptotic cells). In conclusion, compound 133, a 4-isoquinolinamide of 3-O-acetyl-leucovorin acid, was the most cytotoxic compound with EC₅₀ values as low as EC₅₀ = 1.48 μM (A375 melanoma cells) and was also cytotoxic against non-malignant fibroblasts with an NIH 3T3 selectivity index > 91.2.

Xu and colleagues [97] designed and synthesized matrine quinoline derivatives 134a–g (Figure 23) (Table 10), using cisplatin as positive drug control, and evaluated compounds for anticancer activity against HepG2, HeLa, and MDA-MB-231 cell lines. Compound 134a–g showed good activity against HepG2, HeLa and MDA MB-231 cell lines with IC₅₀ below 25 μM.

Figure 23. The chemical structures of anticancer compounds 129–134.

Insuasty and colleagues [98] synthesized a series of quinoline-based symmetrical and asymmetrical bis-acetal compounds 135–136 (Figure 24) (Table 10). These compounds were evaluated for their in vitro cytotoxic activity against different human cancer cell lines. Compounds 135, 136a, 136d, 136f, and 136g showed the highest activity, while compounds 136b, 136c, and 136e showed moderate activity. Symmetrical N-butyl quinoline chalcone 135 and asymmetrical bis-chalcone 136g exhibited the highest cytotoxicity with overall GI₅₀ values ranging from 0.16 to 5.45 μM, with excessive activity of HCT-116 (GI₅₀ = 0.16 μM) and HT29 (GI₅₀ = 0.42 μM) (colon cancer). Notably, several GI₅₀ values of these compounds were superior to the reference drugs doxorubicin and 5-FU.

Mohassab and colleagues [99] developed novel quinoline/chalcone derivatives 137–139 (Figure 24) (Table 10) and tested them in vitro against a panel of cancer cell lines and EGFR and BRAFV600E anticancer targets. The most active compounds 137a–b and 138a–b effectively inhibited cancer cell growth. After compound 137b, the difference observed between compounds 139a–b was almost comparable and extreme in terms of anticancer activity with GI₅₀ cell lines of 3.625 μM and 4.550 μM, respectively. In contrast, compound 137b showed the highest activity among all the new compounds with a GI₅₀ of 3.325 μM to inhibit the growth of cancer cells.

Zeng and colleagues [100] synthesized parthenolide quinoline heterodimer 140 (Figure 24) (Table 10) and evaluated the compounds for in vitro antiproliferative activity in five human cancer cell lines, HCT116, U85MG, HepG2, HepG2, BGC823, and PC9. Paclitaxel (PTX) was used as an experimental control. PTL and MCL were used as positive controls for their inhibition of NF-κB and STAT3. The results showed that compound 140 exhibited higher cytotoxicity than PTL and MMB for all five cell lines. IC₅₀ values range from 2.11 to 5.23 μM/L, respectively.

Mogrol (CF: C₃₀H₅₂O₄, MW: 476.73, (3β,9β,10α,11α,24R)-9-Methyl-19-norlanost-5-ene-3,11,24,25-tetrol) is a polysaccharide of Luo Han Guo saponin, which is the main active component of Luo Han Guo. Song and his colleagues [101] synthesized mogrol quinoline derivatives 141–142 (Figure 24) (Table 10) and evaluated the in vitro cytotoxicity of the compounds against human lung cancer cell lines A549 and NCI-H460. A quinoline scaffold was introduced to generate 141a–c and 142a–d, and the cyclic A-fusion derivative 142a–d exhibited higher activity than 141a–c against the tested cell lines. Compounds 141a–b and 142a–d showed stronger inhibitory activity than mogrol against A549 with IC₅₀ values ranging from 12.94 to 19.24 μM. The R₁ and R₂ substituents on the quinoline moiety significantly affected the activity, and the presence of the halogen atom resulted in a decrease in cytotoxic activity. All quinoline derivatives except compound 141c were more active than mogrol against NCI-H460, while compound 142a showed the highest activity with an IC₅₀ value of 17.13 μM.

Celastrol (CF: C₂₉H₃₈O₄, MW: 450.61, (9β,13α,14β,20α)-3-Hydroxy-9,13-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic acid) is a pentacyclic triterpene from Tripterygia Wilfordil Hook. f., a pentacyclic triterpene. Shang and colleagues [102] synthesized celastrol quinoline derivative 143 (Figure 24) (Table 10) and evaluated the toxicity of this compound on Hep3B cells, with celastrol being used as a positive control. Compound 143 with a 3-quinoxyl ethyl substituent had the strongest HIF-1a inhibitory activity in this study, with an IC₅₀ value of only 0.05 μM, which was 5-fold higher than the activity of celastrol (IC₅₀ = 0.25 μM). In addition, Western blot results showed that compound 143 could inhibit the expression of HIF-1a protein. Further experiments showed that 143 significantly inhibited the formation of Hep3B cell colonies, hindered cell migration, and induced apoptosis to some extent. Compound 143 (10 mg/kg) had good in vivo antitumor activity in a mouse tumor xenograft model with an inhibition rate of 74.03%, which was superior to the reference compound 5-FU inhibition rate (59.58%).

Figure 24. The chemical structures of anticancer compounds 135–143.

Dong and colleagues [103] synthesized 6,7,10-trimethoxy-α-naphthoflavone-quinoline derivative 144 (Figure 25) (Table 10) and screened it against the CYP1 enzyme to assess whether larger substituents could enhance the inhibitory activity against CYP1B1. Compound 144 selectively inhibited CYP1B1. IC₅₀ values of 117.6, 1.0 and >1000 μM for CYP1A1, CYP1B1, and CYP1A2, respectively.

Guan and colleagues [104] synthesized chalcone quinoline derivatives 145–146 (Figure 25) (Table 10) and evaluated the in vitro antiproliferative activity of the compounds against MGC-803, HCT-116, and MCF-7. The chemotherapy medication 5-Fluorouracil (5-Fu) was used as a positive control. Most quinoline–chalcone derivatives showed strong antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells with IC₅₀ values < 20 μM. Among them, compound 145e showed the most remarkable inhibitory effect on MGC803, HCT-116, and MCF-7 cells with IC₅₀ values of 1.3, 5.34, and 5.21 μM, respectively, which was much lower than that of 5-Fu (IC₅₀ values = 6.22 μM, 0.4 μM, and 11.1 μM, respectively). Thus, the antiproliferative activity of compound 145e on MGC803 cells, structure–activity relationships suggests that the type and position of the substituent (R1) on the chalcone moiety (A ring) have an important effect on its antiproliferative activity. Compared with 145f, the activity of compounds 145a–e with the electron-donating group of A ring is higher than that of unsubstituted A ring. However, compounds 145g and 145i and the compound with an electron-withdrawing group of A ring inhibit proliferation more actively than the compound 145f. In addition, the position of the substituent (R) is also important. When the substituent (R) is located at the 3 position of the chalcone group (A ring), the inhibitory activity of the compound is lower than when the substituent (R₁) is located at the 3 position of the A ring (compound 145b vs. 145c, 145g vs. 145i, and 145h vs. 145i). However, compound 145e with the 3,4,5-triOCH substituent of the chalcone group (A ring) showed better activity. The relationship between the electron-donating group and an electron-withdrawing group of the chalcone group (A ring) and the inhibition of MGC-803 cells is 3,4,5-triOCH₃ > 3,4-diOCH₃ > 4-CH₃ > 4-bromo > 4-OCH₃ > 3-OCH₃ > 3-Br > H > 4-Cl > 3-Cl. Next, the impact of R₂ is further explored. The results showed that the inhibitory activity of compounds 146a–f decreased when the H group was substituted with CH₃ or CH₃CH₂ substituents (compounds 146a vs. 145f, 146b vs. 145a, 146c vs. 145d, 146d vs. 145g, 146e vs. 145e, and 146f vs. 145e), indicating that the R₂ substituent does not increase the inhibitory potency. The in vitro antiproliferative activities of novel target compounds 145a–i and 146a–f were evaluated against the human cell lines MGC-803 (gastric cancer), HCT-116 (colon cancer), and MCF-7 (breast cancer), with 5-fluorouracil (5-Fu) as a positive control. The results showed that most quinoline–chalcone derivatives have strong antiproliferative activities against the MGC-803HCT-116 and MCF-7 cells, with IC₅₀ values < 20uM. Among them, compound 145e has the greatest inhibitory effect on MGC803, HCT-116, and MCF-7 cells, with IC₅₀ values of 1.35.34 and 5.21 μM, respectively, which is much lower than that of 5-Fu (IC₅₀ value = 6.22 μm) of 0.4 μM, 5.21 μM, and 11.1 μM, respectively, indicating that compound 145e has an inhibitory effect on the activity of three tumor cells. In addition, the MGC-803 cells are more sensitive to most compounds than the HCT-116 and MCF-7 cells. Therefore, according to the structure–activity relationship of the antiproliferative activity of MGC803 cells, the type and position of the substituent (R₁) on the chalcone group (A ring) were related to its antiproliferative activity.

Thorat and colleagues [105] synthesized the 6-amino flavonoid quinoline derivative 147 (Figure 25) (Table 10) and evaluated the in vitro antiproliferative efficacy of compound 147 against MCF-7 and human A-549. Doxorubicin was used as a positive control. Compound 147 showed satisfactory anticancer activity against MCF-7, with 44.76% inhibition against this cancer cell line. Compound 147 also showed acceptable antiproliferative activity against A-549, exhibiting the cell at 44.26% under a concentration of 10 μM.

Jyothi and colleagues [106] synthesized coumarin quinoline derivatives 148a–c (Figure 25) (Table 10) and evaluated their activities against the human-derived cancer cells ACHN, A375, SIHA, Skov3, EAC, and NIH3T3. However, compounds 148a–c did not demonstrate any anticancer activity.

Herrmann and colleagues [107] synthesized artemisinin-quinoline derivatives 149–153 (Figure 25) (Table 10) and analyzed their inhibitory activity in vitro against leukemia cell lines CCRF-CEM, RPMI-8226, K562, HL-60, and MOLT 4. The data showed that artemisinins 149–151 and synthetic peroxo-quinolines 152 and 153 were the most active compounds against the K562 leukemia cell line in vitro, with IC₅₀ values of 37.3 and 83.0 μM, respectively.

Figure 25. The chemical structures of anticancer compounds 144–153.

Table 10. Quinoline derivatives with anticancer activity.

Compd.	Activity	Target	Origin	Ref
43	Anti- TK10 TGI = 18.5 μM Anti- UACC62 TGI = 17.43 μM Anti- MCF7 TGI = 2.92 μM	-	synthetic	[39]
44	-	-	synthetic	[39]
71a	Determine growth inhibitory activity = 85%	-	synthetic	[59]
71b	Determine growth inhibitory activity = 77%	-	synthetic	[59]
77	Anti-melanoma GI₅₀ = 0.134 μM	-	synthetic	[63]
78a	Anti- Ae549 IC₅₀ = 15.4 μM Anti- A375 IC₅₀ = 14.5 μM Anti- MCF-7 IC₅₀ = 13.8 μM Anti- HT-29 IC₅₀ = 12.3 μM Anti- ACHN IC₅₀ = 10.8 μM	DNA topoisomerase-IIa	synthetic	[64]
78b	Anti- Ae549 IC₅₀ = 13.4 μM Anti- A375 IC₅₀ = 7.7 μM Anti- MCF-7 IC₅₀ = 11.2 μM Anti- HT-29 IC₅₀ = 7.75 μM Anti- ACHN IC₅₀ = 15.7 μM	DNA topoisomerase-IIa	synthetic	[64]
79a	Anti- Ae549 IC₅₀ = 10.6 μM Anti- A375 IC₅₀ = 10.3 μM Anti- MCF-7 IC₅₀ = 8.6 μM Anti- HT-29 IC₅₀ = 11.8 μM Anti- ACHN IC₅₀ = 10.7 μM	DNA topoisomerase-IIa	synthetic	[64]
79b	Anti- Ae549 IC₅₀ = 7.7 μM Anti- A375 IC₅₀ = 6.8 μM Anti- MCF-7 IC₅₀ = 2.2 μM Anti- HT-29 IC₅₀ = 8.9 μM Anti- ACHN IC₅₀ = 9.46 μM	DNA topoisomerase-IIa	synthetic	[64]
80	Anti- angiogenesis inhibition rate ranged between 50 and 60%	-	synthetic	[65]
81	Anti-A549 GI₅₀ = 2.51 μM	Erk1/2 signaling pathway	synthetic	[66]
82	Anti-HepG2 IC₅₀ = 16.03 μM Anti-HeLa IC₅₀ = 0.60 μM Anti-A549 IC₅₀ = 10.05 μM Anti-BGC-823 IC₅₀ = 17.41 μM Anti-HL-7702 IC₅₀ = 41.77 μM	Caspase-3	synthetic	[67]
83	Anti-HepG2 IC₅₀ = 9.18 μM Anti-HeLa IC₅₀ = 20.53 μM Anti-A549 IC₅₀ = 19.20 μM Anti-BGC-823 IC₅₀ = 28.81 μM Anti-HL-7702 IC₅₀ = 20.09 μM	Caspase-3	synthetic	[67]
84	Anti-HL-60 IC₅₀ = 0.1 μM Anti-MCF-7 IC₅₀ = 0.1 μM Anti-T-47D IC₅₀ = 0.1 μM Anti-LNCaP IC₅₀ = 2.0 μM Anti-WEHI-3 IC₅₀ = 1.1 μM	-	synthetic	[68]
85	Anti-SGC 7901 IC₅₀ = 1 μM	Topoisomerase II	synthetic	[69]
86	Anti-MCF-7 IC₅₀ = 181.478 μM Anti-MCF-7/ADR IC₅₀ = 96.523 μM Anti-SW1990 IC₅₀ = 111.837 μM Anti-SMMC-7721 IC₅₀ = 75.546 μM	-	synthetic	[70]
87	Anti-HepG2 IC₅₀ = 8.40 μM Anti-A431 IC₅₀ = 11.56 μM Anti-A549 IC₅₀ = 4.33 μM Anti-MCF 7 IC₅₀ = 5.99 μM Anti-HCT 116 IC₅₀ = 3.48 μM	-	synthetic	[71]
88	Anti-MDA-MB 468 IC₅₀ = 0.12 μM	Microtubule	synthetic	[72]
89	Anti-SKOV3 IC₅₀ = 12.8 μM	oxygen species (ROS)	synthetic	[73]
90	Anti-Bel-7404 IC₅₀ = 28.7 µmol/L Anti-SGC-7901 IC₅₀ = 17.9 µmol/L	-	synthetic	[74]
91	Anti-HT-29 IC₅₀ = 14.1 μmol/L Anti-HeLa IC₅₀ = 9.1 μmol/L Anti-SGC-7901 IC₅₀ = 8.2 μmol/L	-	synthetic	[75]
92a	Anti-Hela 30 μM IC₅₀ = 59.5 μM	Caspase-3	synthetic	[76]
92b	Anti-T47D 30 μM IC₅₀ = 48.1 μM	Caspase-3	synthetic	[76]
92c	Anti-T47D 30 μM IC₅₀ = 63.0 μM	Caspase-3	synthetic	[76]
93a	Anti- MCF7 30 μM IC₅₀ = 31.5 μM	Caspase-3	synthetic	[76]
93b	Anti-SiHa 10 μM IC₅₀ = 24.7 μM	Caspase-3	synthetic	[76]
93c	Anti-MCF7 30 μM IC₅₀ = 35.6 μM	Caspase-3	synthetic	[76]
93d	Anti- SiHa 30 μM IC₅₀ = 25.6 μM	Caspase-3	synthetic	[76]
93e	Anti-Hela 30 μM IC₅₀ = 96.6 μM	Caspase-3	synthetic	[76]
93f	Anti- Hela 30 μM IC₅₀ = 89.4 μM	Caspase-3	synthetic	[76]
94a	Anti-MCF7 30 μM IC₅₀ = 38.6 μM	Caspase-3	synthetic	[76]
94b	Anti-C33A 30 μM IC₅₀ = 61.0 μM	Caspase-3	synthetic	[76]
94c	Anti-MDA-MB-231 30 μM IC₅₀ = 71.2 μM	Caspase-3	synthetic	[76]
94d	-	Caspase-3	synthetic	[76]
94e	Anti-MDA-MB-361 30 μM IC₅₀ = 66.0 μM	Caspase-3	synthetic	[76]
94f	Anti-MDA-MB-361 30 μM IC₅₀ = 68.2 μM	Caspase-3	synthetic	[76]
94g	Anti-MCF7 30 μM IC₅₀ = 62.9 μM	Caspase-3	synthetic	[76]
94h	-	Caspase-3	synthetic	[76]
94i	-	Caspase-3	synthetic	[76]
95a	Anti-C33A 30 μM IC₅₀ = 93.6 μM	Caspase-3	synthetic	[76]
95b	Anti- C33A 30 μM IC₅₀ = 71.0 μM	Caspase-3	synthetic	[76]
95c	Anti-MDA-MB-361 30 μM IC₅₀ = 80.4 μM	Caspase-3	synthetic	[76]
95d	Anti-C33A 30 μM IC₅₀ = 73.1 μM	Caspase-3	synthetic	[76]
95e	Anti-C33A 30 μM IC₅₀ = 86.4 μM	Caspase-3	synthetic	[76]
95f	Anti-C33A 30 μM IC₅₀ = 86.9 μM	Caspase-3	synthetic	[76]
95g	Anti-C33A 30 μM IC₅₀ = 74.7 μM	Caspase-3	synthetic	[76]
95h	Anti-MDA-MB-361 30 μM IC₅₀ = 75.2 μM	Caspase-3	synthetic	[76]
96	Assembly of purified tubulin IC₅₀ = 1.6 μM	Tubulin	synthetic	[77]
97a	Anti-NIH 3T3 EC₅₀ = 0.9 μM	-	synthetic	[78]
97b	Anti-NIH 3T3 EC₅₀ = 2.2 μM	-	synthetic	[78]
97c	Anti-A2780 EC₅₀ = 2.0 μM	-	synthetic	[78]
97d	Anti-A2780 EC₅₀ = 3.5 μM	-	synthetic	[78]
97e	Anti-A2780 EC₅₀ = 0.7 μM	-	synthetic	[78]
97f	Anti-518A2 EC₅₀ = 2.0 μM	-	synthetic	[78]
97g	Anti-NIH 3T3 EC₅₀ = 0.6 μM	-	synthetic	[78]
97h	Anti-NIH 3T3 EC₅₀ = 0.9 μM	-	synthetic	[78]
97i	Anti- NIH 3T3 EC₅₀ = 0.7 μM	-	synthetic	[78]
97j	Anti- MCF7 EC₅₀ = 1.6 μM	-	synthetic	[78]
97k	Anti-A2780 EC₅₀ = 5.1 μM	-	synthetic	[78]
97l	Anti-A2780 EC₅₀ = 6.7 μM	-	synthetic	[78]
98	Anti-A2780 EC₅₀ = 1.2 μM	-	synthetic	[78]
99a	Anti-A2780 IC₅₀ = 8.04 μM	Tubulin	synthetic	[79]
99b	Anti-MCF-7/MX IC₅₀ = 21.48 μM	Tubulin	synthetic	[79]
99c	Anti-A2780 IC₅₀ = 9.19 μM	Tubulin	synthetic	[79]
99d	Anti-A2780 IC₅₀ = 7.98 μM	Tubulin	synthetic	[79]
99e	Anti- A2780RCIS IC₅₀ = 8.15 μM	Tubulin	synthetic	[79]
100	Anti-K562/ADR IC₅₀ = 0.061 μM Anti-K562 IC₅₀ = 0.064 μM	MAPK	synthetic	[80]
101	Anti-K562/ADR IC₅₀ = 0.177 μM Anti-K562 IC₅₀ = 0.064 μM	MAPK	synthetic	[80]
102	Anti-K562/ADR IC₅₀ = 0.034 μM Anti-K562 IC₅₀ = 0.022 μM	MAPK	synthetic	[80]
103	Anti-HL60 IC₅₀ = 8.09 μM Anti-SGC-7901 IC₅₀ = 73.40 μM Anti-MCF-7 IC₅₀ = 19.66 μM Anti-HCT116 IC₅₀ = 14.79 μM Anti-A549 IC₅₀ = 17.61 μM Anti- HaCat IC₅₀ = 11.49 μM	-	synthetic	[81]
104	Anti-Bel-7402 IC₅₀ = 0.96 μM Anti-K562 IC₅₀ = 1.89 μM Anti-MGC-803 IC₅₀ = 1.03 μM Anti-CaEs-17 IC₅₀ = 1.74 μM	-	synthetic	[62]
105a	Anti-HeLa IC₅₀ = 0.37 μM	-	synthetic	[82]
105b	Anti-HeLa IC₅₀ = 0.36 μM	-	synthetic	[82]
105c	Anti-HeLa IC₅₀ = 1.22 μM	-	synthetic	[82]
105d	Anti-MDA-MB-231 IC₅₀ = 0.90 μM	-	synthetic	[82]
106a	Anti-HeLa IC₅₀ = 19.03 μM	-	synthetic	[82]
106b	Anti-HeLa IC₅₀ = 25.78 μM	-	synthetic	[82]
106c	Anti-MDA-MB-231 IC₅₀ = 13.34 μM	-	synthetic	[82]
106d	Anti-MDA-MB-231 IC₅₀ = 17.44 μM	-	synthetic	[82]
106e	Anti-HeLa IC₅₀ = 21.88 μM	-	synthetic	[82]
106f	Anti-HeLa IC₅₀ = 12.27 μM	-	synthetic	[82]
106g	Anti-HeLa IC₅₀ = 13.13 μM	-	synthetic	[82]
106h	Anti-HeLa IC₅₀ = 23.45 μM	-	synthetic	[82]
106i	Anti-HeLa IC₅₀ = 7.16 μM	-	synthetic	[82]
106j	Anti-HeLa IC₅₀ = 26.87 μM	-	synthetic	[82]
106k	Anti-HeLa IC₅₀ = 30.25 μM	-	synthetic	[82]
106l	Anti-HeLa IC₅₀ = 12.45 μM	-	synthetic	[82]
107a	Anti-MDA-MB-231 IC₅₀ = 22.37 μM	-	synthetic	[82]
107b	Anti-HeLa IC₅₀ = 32.13 μM	-	synthetic	[82]
107c	Anti-HeLa IC₅₀ = 7.11 μM	-	synthetic	[82]
107d	Anti-MDA-MB-231 IC₅₀ = 19.39 μM	-	synthetic	[82]
107e	Anti-HeLa IC₅₀ = 28.12 μM	-	synthetic	[82]
107f	Anti-HeLa IC₅₀ = 12.31 μM	-	synthetic	[82]
107g	Anti-MDA-MB-231 IC₅₀ = 23.35 μM	-	synthetic	[82]
107h	Anti-MDA-MB-231 IC₅₀ > 40 μM	-	synthetic	[82]
107i	Anti-HeLa IC₅₀ = 16.29 μM	-	synthetic	[82]
107j	Anti-HeLa IC₅₀ = 28.29 μM	-	synthetic	[82]
107k	Anti-HeLa IC₅₀ = 32.25 μM	-	synthetic	[82]
107l	Anti-HeLa IC₅₀ = 12.09 μM	-	synthetic	[82]
108	Anti-HeLa IC₅₀ = 11.2 μM/L Anti-HT-29 IC₅₀ = 21.3 μM/L Anti-Bel 7404 IC₅₀ = 28.9 μM/L Anti-SGC 7901 IC₅₀ = 10.3 μM/L	-	synthetic	[83]
109	-	-	synthetic	[83]
110	-	Cysteine protease falcipain-2	synthetic	[84]
111	Anti-ERK IC₅₀ = 0.6 μM	ERK2	synthetic	[85]
112	Anti-ERK IC₅₀ = 0.16 μM	ERK2	synthetic	[85]
113	Anti-PC-3 IC₅₀ = 3.12 μM Anti-DU-145 IC₅₀ = 3.99 μM Anti-NCI-H460 IC₅₀ = 3.96 μM Anti-4 T1 IC₅₀ = 1.81 μM	-	synthetic	[86]
114a	Anti-A2780 IC₅₀ = 25 μg/mL	-	synthetic	[87]
114b	Anti-A2780 IC₅₀ = 62 μg/mL	-	synthetic	[87]
115	Anti-MCF-7 GI₅₀ = 38.3 Μm	-	synthetic	[88]
116	Anti-MCF-7 GI₅₀ = 10.5 μM	-	synthetic	[88]
117	Anti-MCF-7 IC₅₀ = 0.41 μM	p53-MDM2	synthetic	[89]
118	Anti-MCF-7 IC₅₀ = 0.89 μM	p53-MDM2	synthetic	[89]
119	Anti-MRC-5 IC₅₀ = 70.8 μM	Tubulin	synthetic	[90]
120	Anti-MCF-7 IC₅₀ = 0.6 μM	Tubulin	synthetic	[90]
121	Anti-A549 IC₅₀ = 2.3 μM	Tubulin	synthetic	[90]
122	Anti-MCF-7 IC₅₀ = 1.0 μM	Tubulin	synthetic	[90]
123a	low antitumor activity	Caspase-3	synthetic	[91]
123b	low antitumor activity	Caspase-3	synthetic	[91]
123c	low antitumor activity	Caspase-3	synthetic	[91]
123d	low antitumor activity	Caspase-3	synthetic	[91]
124a	Anti-HeLa IC₅₀ = 0.37 μM	Ras/Raf/MEK/ERK	synthetic	[92]
124b	Anti-HeLa IC₅₀ = 0.36 μM	Ras/Raf/MEK/ERK	synthetic	[92]
124c	Anti-MDA-MB-231 IC₅₀ = 0.90 μM	Ras/Raf/MEK/ERK	synthetic	[92]
124d	Anti-HeLa IC₅₀ = 1.22 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125a	Anti-HeLa IC₅₀ = 1.18 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125b	Anti-HeLa IC₅₀ = 0.83 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125c	Anti-HeLa IC₅₀ = 0.99 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125d	Anti-HeLa IC₅₀ = 0.08 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125e	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125f	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125g	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
125h	Anti-HeLa IC₅₀ = 46.01 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126a	Anti-MDA-MB-231 IC₅₀ = 5.32 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126b	Anti-MDA-MB-231 IC₅₀ = 12.25 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126c	Anti-MDA-MB-231 IC₅₀ = 13.17 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126d	Anti-HeLa IC₅₀ = 4.28 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126e	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126f	Anti-HeLa IC₅₀ = 30.94 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126g	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
126h	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127a	Anti-MDA-MB-231 IC₅₀ = 18.75 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127b	Anti-HeLa IC₅₀ = 12.82 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127c	Anti-MDA-MB-231 IC₅₀ = 31.57 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127d	Anti-HeLa IC₅₀ = 10.92 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127e	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127f	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127g	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
127h	Anti-HeLa IC₅₀ > 50 μM	Ras/Raf/MEK/ERK	synthetic	[92]
128a	Anti-A549 IC₅₀ = 15.21 μM	-	synthetic	[93]
128b	Anti-A549 IC₅₀ = 12.65 μM	-	synthetic	[93]
128c	Anti-A549 IC₅₀ = 13.34 μM	-	synthetic	[93]
128d	Anti-A549 IC₅₀ = 12.23 μM	-	synthetic	[93]
128e	Anti-A549 IC₅₀ = 8.34 μM	-	synthetic	[93]
128f	Anti-A549 IC₅₀ = 5.34 μM	-	synthetic	[93]
128g	Anti-H1975 IC₅₀ = 12.95 μM	-	synthetic	[93]
128h	Anti-H1975 IC₅₀ = 14.31 μM	-	synthetic	[93]
128i	Anti-A549 IC₅₀ = 10.28 μM	-	synthetic	[93]
128j	Anti-A549 IC₅₀ = 9.01 μM	-	synthetic	[93]
128k	Anti-A549 IC₅₀ = 23.91 μM	-	synthetic	[93]
128l	Anti-A431 IC₅₀ = 12.56 μM	-	synthetic	[93]
129a	Anti-K562 IC₅₀ = 0.850 μM	Tubulin	synthetic	[94]
129b	Anti-K562 IC₅₀ = 0.011 μM	Tubulin	synthetic	[94]
129c	Anti-K562 IC₅₀ = 0.127 μM	Tubulin	synthetic	[94]
129d	Anti-K562 IC₅₀ = 0.009 μM	Tubulin	synthetic	[94]
129e	Anti-K562 IC₅₀ = 0.108 μM	Tubulin	synthetic	[94]
129f	Anti-K562 IC₅₀ = 1.055 μM	Tubulin	synthetic	[94]
129g	Anti-K562 IC₅₀ = 0.069 μM	Tubulin	synthetic	[94]
129h	Anti-K562 IC₅₀ = 0.563 μM	Tubulin	synthetic	[94]
129i	Anti-K562 IC₅₀ > 1 μM	Tubulin	synthetic	[94]
129j	Anti-K562 IC₅₀ > 1 μM	Tubulin	synthetic	[94]
129k	Anti-K562 IC₅₀ > 1 μM	Tubulin	synthetic	[94]
129l	Anti-K562 IC₅₀ = 0.346 μM	Tubulin	synthetic	[94]
129m	Anti-K562 IC₅₀ = 0.074 μM	Tubulin	synthetic	[94]
129n	Anti-K562 IC₅₀ > 1 μM	Tubulin	synthetic	[94]
129o	Anti-K562 IC₅₀ > 1 μM	Tubulin	synthetic	[94]
130a	Anti-K562 IC₅₀ = 0.040 μM	Tubulin	synthetic	[94]
130b	Anti-K562 IC₅₀ = 0.026 μM	Tubulin	synthetic	[94]
130c	Anti-K562 IC₅₀ = 0.015 μM	Tubulin	synthetic	[94]
130d	Anti-K562 IC₅₀ = 1.239 μM	Tubulin	synthetic	[94]
131	Anti-HCT116 IC₅₀ = 3.31 μM Anti-U87-MG IC₅₀ = 1.47 μM Anti-HepG2 IC₅₀ = 3.66 μM Anti-BGC823 IC₅₀ = 1.77 μM Anti-PC9 IC₅₀ = 3.12 μM	NF-κB	synthetic	[95]
132	Anti-HepG2 IC₅₀ = 14.3 μM	-	synthetic	[96]
133	Anti-HepG2 IC₅₀ = 9.2 μM	-	synthetic	[96]
134a	Anti-HepG2 IC₅₀ = 14.3 μM	Hsp90^N	synthetic	[97]
134b	Anti-HepG2 IC₅₀ = 9.2 μM	Hsp90^N	synthetic	[97]
134c	Anti-HepG2 IC₅₀ = 10.9 μM	Hsp90^N	synthetic	[97]
134d	Anti-HepG2 IC₅₀ = 13.1 μM	Hsp90^N	synthetic	[97]
134e	Anti-HepG2 IC₅₀ = 6.4 μM	Hsp90^N	synthetic	[97]
134f	Anti-Hela IC₅₀ = 6.9 μM	Hsp90^N	synthetic	[97]
134g	Anti-HepG2 IC₅₀ = 16.1 μM	Hsp90^N	synthetic	[97]
135	Anti-HCT-116 IC₅₀ = 0.16 μM	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136a	Anti-HCT-116 IC₅₀ = 1.55 μM	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136b	Anti-RPMI-8226 IC₅₀ = 1.29 μM	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136c	Anti-MDA-MB-435 IC₅₀ = 0.30 μM	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136d	Anti-HCT-116 IC₅₀ = 0.26 μM	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136e	-	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136f	-	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
136g	-	HER1, HER2, proteasome, and hTS appear as promising targets for these compounds	synthetic	[98]
137a	Anti-A549 IC₅₀ = 6.1 μM	EGFR, BRAF^V600E	synthetic	[99]
137b	Anti-Panc-1 IC₅₀ = 2.9 μM	EGFR, BRAF^V600E	synthetic	[99]
138a	Anti-MCF-7 IC₅₀ = 23.1 μM	EGFR, BRAF^V600E	synthetic	[99]
138b	Anti-MCF-7 IC₅₀ = 29.5 μM	EGFR, BRAF^V600E	synthetic	[99]
139a	Anti-MCF-7 IC₅₀ = 3.2 μM	EGFR, BRAF^V600E	synthetic	[99]
139b	Anti-Panc-1 IC₅₀ = 4.5 μM	EGFR, BRAF^V600E	synthetic	[99]
140	Anti-HCT116 IC₅₀ = 2.11 μM Anti-U87MG IC₅₀ = 2.47 μM Anti-HepG2 IC₅₀ = 4.71 μM Anti-BGC823 IC₅₀ = 5.23 μM Anti-PC9 IC₅₀ = 3.00 μM	NF-κB, STAT3	synthetic	[100]
141a	Anti-A549 IC₅₀ = 19.24 μM Anti-NCI-H460 IC₅₀ = 24.61 μM		synthetic	[101]
141b	Anti-A549 IC₅₀ = 18.21 μM	STAT3	synthetic	[101]
141c	-	STAT3	synthetic	[101]
142a	Anti-A549 IC₅₀ = 13.78 μM Anti-NCI-H460 IC₅₀ = 17.13 μM	STAT3	synthetic	[101]
142b	Anti-A549 IC₅₀ = 14.34 μM Anti-NCI-H460 IC₅₀ = 18.32 μM	STAT3	synthetic	[101]
142c	Anti-A549 IC₅₀ = 12.94 μM	STAT3	synthetic	[101]
142d	Anti-A549 IC₅₀ = 13.05 μM	STAT3	synthetic	[101]
143	Anti-HIF-1a IC₅₀ = 0.05 μM	HIF-1a	synthetic	[102]
144	Anti-CYP1A1 IC₅₀ = 117.6 μM Anti-CYP1B1 IC₅₀ = 1.0 μM Anti-CYP1A2 IC₅₀ > 1000 μM	CYP1B1	synthetic	[103]
145a	Anti-MGC-803 IC₅₀ = 1.86 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145b	Anti-MGC-803 IC₅₀ = 2.39 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145c	Anti-MGC-803 IC₅₀ = 2.63 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145d	Anti-MGC-803 IC₅₀ = 1.62 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145e	Anti-MGC-803 IC₅₀ = 1.38 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145f	Anti-MGC-803 IC₅₀ = 3.24 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145g	Anti-MGC-803 IC₅₀ = 3.82 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145h	Anti-MGC-803 IC₅₀ = 2.28 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145i	Anti-MGC-803 IC₅₀ = 4.25 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
145j	Anti-MGC-803 IC₅₀ = 3.22 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
146a	Anti-MGC-803 IC₅₀ = 8.26 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
146b	Anti-MGC-803 IC₅₀ = 4.63 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
146c	Anti-MGC-803 IC₅₀ = 4.54 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
146d	Anti-MGC-803 IC₅₀ = 8.25 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
146e	Anti-MGC-803 IC₅₀ = 3.73 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
146f	Anti-MGC-803 IC₅₀ = 10.21 μM	Caspase3/9, cleaved-PARP	synthetic	[104]
147	10 μM Anti-MCF-7 Inhibition = 44.76% Anti-A549 Inhibition = 44.26%	Topoisomerase II	synthetic	[105]
148a	Anti-EAC IC₅₀ = 62.25 μM	Vascular Endothelial Growth Factor (VEGF)	synthetic	[106]
148b	Anti-A375 IC₅₀ = 69.52 μM	Vascular Endothelial Growth Factor (VEGF)	synthetic	[106]
148c	Anti-ACHN IC₅₀ = 62.65 μM	Vascular Endothelial Growth Factor (VEGF)	synthetic	[106]
149	Anti-MOLT-4 EC₅₀ = 33.4 μM	-	synthetic	[107]
150	Anti-RPMI-8226 EC₅₀ = 23.3 μM	-	synthetic	[107]
151	Anti-MOLT-4 EC₅₀ = 33.5 μM	-	synthetic	[107]
152	Anti-RPMI-8226 EC₅₀ = 16.3 μM	-	synthetic	[107]
153	Anti-MOLT-4 EC₅₀ = 24.4 μM	-	synthetic	[107]

Summary: Among the recognized anticancer drugs, such as camptothecin and cabozantinib, quinoline scaffolds are contained. Therefore, quinoline has been widely studied and is considered to be an efficient chemical structure in antitumor research. At present, among all the biological activities related to quinoline, anticancer activity has been reported the most. Anticancer drugs containing quinoline structure are divided into the following three main structural categories: non-fused quinoline (such as cabozantinib); fusion quinoline compounds (such as camptothecin); metal complexes with quinoline or phenanthroline ligands.

The compounds containing quinoline structure antitumor activity are mainly the first two, and most of them can show strong antitumor activity. For example, for HeLa cells, 105a and 105b had the strongest activity (IC₅₀ values were 0.37 and 0.36 μM, respectively). For MCF-7 cells, 120 had the strongest activity (IC₅₀ values were 0.60 μM). For A549 cells, 121 had the strongest activity (IC₅₀ values were 2.3 μM). In addition, the mechanism of action is mainly aimed at the mechanism of cell division, or the induction of apoptosis. However, the research on the mechanism of action is not deep enough and there is still a lack of in vivo research.

4. Conclusions

Natural products have always been a rich source of effective drugs and will continue to be an important source of new pharmacological lead drugs. However, natural physiologically active chemicals may have adverse pharmacological properties that limit their use, such as cytotoxicity, excessive lipophilicity, or poor oral absorption. Another major obstacle to the use of natural products in drug research is the inability to obtain these derivatives from sustainable sources. The quinoline ring has many medicinal values, and it is becoming more and more popular as a multifunctional drug chemical scaffold. Due to the wide range of biological functions of quinoline molecules, natural compounds with structural changes are often used as quinoline molecules and developed into key heterocyclic scaffolds to help discover new drugs with new structures and new processes. We have been looking for new natural product quinoline derivatives that can produce potential biological activity. This literature review shows that quinoline scaffolds have considerable biological relevance in anti-osteoporosis, anti-virus, anti-diabetes, anti-inflammation, anti-thrombosis, anti-parasitic, antimalarial, antibacterial, and anticancer studies, which leads to the emergence of many efficient quinoline compounds in many therapeutic fields. Among them, anti-malaria and antitumor are the two most popular research fields. Observing quinoline-based antimalarial drugs, it can be seen that most of them still have traditional pharmacodynamic units, which also exist in quinoline antimalarial drugs, such as chloroquine, amodiaquine, and primaquine. In cancer research, there are many types of tumors, and the occurrence and progression of tumors are also complex. There are many cancer-related targets, and the chemical drug space exploration around quinoline antitumor drugs has great diversity, and it is easier to develop antitumor drugs with strong activity and small side effects. In short, in the future research of medicinal chemistry, quinoline drugs will continue to be used as superior scaffolds for the development of derivatives with high biological activity, among which antimalarial and antitumor development are of the greatest value. This review provides a comprehensive data resource of natural product quinoline derivatives for pharmaceutical chemists engaged in drug design and development, which is helpful for pharmaceutical companies to carry out richer and more organized drug discovery actions in experimental research so that the scientific community can reasonably design and develop various optimized, new, and targeted quinoline derivatives.

Author Contributions

Conceptualization and review methodologies—Y.-Q.Z. and X.L. Original draft writing—Y.-Q.Z. and T.L. Editing—All authors. Figure creation—Y.-Q.Z. Revision—T.L. and Z.-S.Q. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Educational Department of Liaoning Province (No. LJKMZ20221801), Doctoral Research Foundation of Shenyang Medical College (No. 20205041), Higher Education Discipline Innovation Project (D18012), National Natural Science Foundation of China (No. 81960626, 82060628, 82204310), Key Projects of Jilin Province Science and Technology Development Plan (No. 20200404130YY), Jilin Scientific and Technological Development Program (No. YDZJ202301ZYTS440, YDZJ202301ZYTS143), Education Department Project of Jilin (JJKH20220559KJ, JJKH20220563KJ).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

3D7strain	Plasmodium falciparum
ACHE	Acetylcholinesterase
ACI	Coccidiosis inhibition rate of Eimeria tenella
ALP	Alkaline phosphatase
ALT	Alanine aminotransferase
AST	Aspartate aminotransferase
BCHE	Cholinesterase
BMP-2	Bone morphogenetic protein-2
DMSO	Dimethyl sulfoxide
FMR	Insecticidal inhibition rate
FRD	Fumarate reductase
FXa	Activation of X factor
HDL-C	High-density lipoprotein cholesterol
IL-6	Interleukin-6
KM mice	Kunming mice
LPS	Lipopolysaccharides
MR	The mite inhibition rate
OA	Oleanolic acid
OCLs	Osteoclast-like multinucleated cells
OCN	Osteoblast secretory protein
PC-3 cells	Human prostate cancer cell line
RUNX-2	Runt-related transcription factor-2
SNB-19	Human glioma adherent cell line
THP1 cells	Human monocytic leukemia
U-937 cells	Cell line exhibiting monocyte morphology

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Zhao, Y.-Q.; Li, X.; Guo, H.-Y.; Shen, Q.-K.; Quan, Z.-S.; Luan, T. Application of Quinoline Ring in Structural Modification of Natural Products. Molecules 2023, 28, 6478. https://doi.org/10.3390/molecules28186478

AMA Style

Zhao Y-Q, Li X, Guo H-Y, Shen Q-K, Quan Z-S, Luan T. Application of Quinoline Ring in Structural Modification of Natural Products. Molecules. 2023; 28(18):6478. https://doi.org/10.3390/molecules28186478

Chicago/Turabian Style

Zhao, Yu-Qing, Xiaoting Li, Hong-Yan Guo, Qing-Kun Shen, Zhe-Shan Quan, and Tian Luan. 2023. "Application of Quinoline Ring in Structural Modification of Natural Products" Molecules 28, no. 18: 6478. https://doi.org/10.3390/molecules28186478

APA Style

Zhao, Y.-Q., Li, X., Guo, H.-Y., Shen, Q.-K., Quan, Z.-S., & Luan, T. (2023). Application of Quinoline Ring in Structural Modification of Natural Products. Molecules, 28(18), 6478. https://doi.org/10.3390/molecules28186478

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Application of Quinoline Ring in Structural Modification of Natural Products

Abstract

1. Introduction

2. Method

3. Pharmacological Activities

3.1. Anti-Alzheimer’s Disease Activity

3.2. Anti-Osteoporosis Activity

3.3. Anti-Viral Activity

3.4. Anti-Hyperglycemic Activity

3.5. Anti-Inflammatory Activity

3.6. Antithrombotic Activity

3.7. Anti-Parasitic Activity

3.8. Antimalarial Activity

3.9. Antibacterial Activity

3.10. Anticancer Activity

4. Conclusions

Author Contributions

Funding

Conflicts of Interest

Abbreviations

References

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