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Synthesis and Application of Quinolines and Quinoline Derivatives

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 31936

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Guest Editor
Institute of Chemistry, Faculty of Mathematics, Physics and Chemistry, University of Silesia, Szkolna 9, Katowice, Poland
Interests: quinoline chemistry and applications; anticancer agents; antifungals; drug design
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Special Issue Information

Dear Colleagues,

Quinoline moiety is one of the most often recognized fragments in bioactive compounds. Soon after it was first isolated, quinoline was identified in various pharmaceutically important alkaloids, like quinine and cinchonine. In addition to this, synthetic procedures were developed, further increasing research. Since then, thousands of scientific papers have been published on this topic. Today, the knowledge gathered in last 180 years is the basis for more rational design novel substances and materials. Quinoline derivatives are known for their exceptionally broad spectrum of activity, including antimicrobial, antiviral and anticancer potency. Among literally each class of the most important small molecule drugs, a quinoline ring can be noticed. Several derivatives were also exploited as dyes, molecular sensors or intelligent materials. Undoubtedly, the good synthetic availability of wide range structural derivatives and manipulation of their electronic properties is the reason for this popularity of quinoline fragment. Thus, in this current Special Issue, original research papers and reviews on every aspect of synthesis and application of quinoline derivatives will be considered. Short communications on the hot topics of this field of ever growing knowledge are also warmly welcomed.

Prof. Dr. Robert Musioł
Guest Editor

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Keywords

  • Quinoline
  • Quinoline antifungals
  • anticancer quinolines
  • quinoline as antimicrobial agents
  • quinoline derivatives in medicinal chemistry
  • quinoline synthesis
  • quinoline as privileged structure
  • quinoline derivatives from natural sources

Published Papers (8 papers)

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Research

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17 pages, 12031 KiB  
Article
Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies
by Sergiy M. Kovalenko, Oleksandr G. Drushlyak, Svitlana V. Shishkina, Irina S. Konovalova, Illia O. Mariutsa, Natalya D. Bunyatyan, Dmitry V. Kravchenko, Vladimir V. Ivanov, Alexandre V. Ivachtchenko and Thierry Langer
Molecules 2020, 25(18), 4238; https://doi.org/10.3390/molecules25184238 - 16 Sep 2020
Cited by 1 | Viewed by 2985
Abstract
Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I [...] Read more.
Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I led to the formation of both O- and N-methylation products mixture-methyl 4-methoxy-2-(methylthio)quinoline-3-carboxylate and methyl 1-methyl-2-(methylthio)-4-oxo-1,4-dihydroquinoline-3-carboxylate with a predominance of O-methylated product. The structure of synthesized compounds was confirmed by means of elemental analysis, 1H-NMR, 13C-NMR, LC/MS, and single-crystal X-ray diffraction. The quantum chemical calculations of geometry and electron structure of methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate’s anion were carried out. According to molecular docking simulations, the studied compounds can be considered as potent inhibitors of Hepatitis B Virus replication. Experimental in vitro biological studies confirmed that studied compounds demonstrated high inhibition of HBV replication in 10 µM concentration. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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27 pages, 4301 KiB  
Article
8-Hydroxyquinoline Glycoconjugates Containing Sulfur at the Sugar Anomeric Position—Synthesis and Preliminary Evaluation of Their Cytotoxicity
by Monika Krawczyk, Gabriela Pastuch-Gawołek, Agnieszka Hadasik and Karol Erfurt
Molecules 2020, 25(18), 4174; https://doi.org/10.3390/molecules25184174 - 11 Sep 2020
Cited by 13 | Viewed by 2816
Abstract
One of the main factors limiting the effectiveness of many drugs is the difficulty of their delivery to their target site in the cell and achieving the desired therapeutic dose. Moreover, the accumulation of the drug in healthy tissue can lead to serious [...] Read more.
One of the main factors limiting the effectiveness of many drugs is the difficulty of their delivery to their target site in the cell and achieving the desired therapeutic dose. Moreover, the accumulation of the drug in healthy tissue can lead to serious side effects. The way to improve the selectivity of a drug to the cancer cells seems to be its conjugation with a sugar molecule, which should facilitate its selective transport through GLUT transporters (glucose transporters), whose overexpression is seen in some types of cancer. This was the idea behind the synthesis of 8-hydroxyquinoline (8-HQ) derivative glycoconjugates, for which 1-thiosugar derivatives were used as sugar moiety donors. It was expected that the introduction of a sulfur atom instead of an oxygen atom into the anomeric position of the sugar would increase the stability of the obtained glycoconjugates against untimely hydrolytic cleavage. The anticancer activity of new compounds was determined based on the results of the MTT cytotoxicity tests. Because of the assumption that the activity of this type of compounds was based on metal ion chelation, the effect of the addition of copper ions on cell proliferation was tested for some of them. It turned out that cancer cells treated with glycoconjugates in the presence of Cu2+ had a much slower growth rate compared to cells treated with free glycoconjugates in the absence of copper. The highest cytotoxic activity of the compounds was observed against the MCF-7 cell line. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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28 pages, 7089 KiB  
Article
One-Pot Multicomponent Synthesis and Bioevaluation of Tetrahydroquinoline Derivatives as Potential Antioxidants, α-Amylase Enzyme Inhibitors, Anti-Cancerous and Anti-Inflammatory Agents
by Samra Farooq, Aqsa Mazhar, Areej Ghouri, Ihsan-Ul-Haq and Naseem Ullah
Molecules 2020, 25(11), 2710; https://doi.org/10.3390/molecules25112710 - 11 Jun 2020
Cited by 14 | Viewed by 4826
Abstract
Mankind has always suffered from multiple diseases. Therefore, there has been a rigorous need in the field of medicinal chemistry for the design and discovery of new and potent molecular entities. In this work, thirteen tetrahydroquinoline derivatives were synthesized and evaluated biologically for [...] Read more.
Mankind has always suffered from multiple diseases. Therefore, there has been a rigorous need in the field of medicinal chemistry for the design and discovery of new and potent molecular entities. In this work, thirteen tetrahydroquinoline derivatives were synthesized and evaluated biologically for their antioxidant, α-amylase enzyme inhibitory, anti-proliferative and anti-inflammatory activities. SF8 showed the lowest IC50 of 29.19 ± 0.25 µg/mL by scavenging DPPH free radicals. SF5 showed significant antioxidant activity in total antioxidant capacity (TAC) and total reducing power (TRP) assays. SF5 and SF9 showed the maximum inhibition of α-amylase enzyme i.e., 97.47% and 89.93%, respectively, at 200 µg/mL concentration. Five compounds were shortlisted to determine their anti-proliferative potential against Hep-2C cells. The study was conducted for 24, 48 and 72 h. SF8 showed significant results, having an IC50 value of 11.9 ± 1.04 µM at 72 h when compared with standard cisplatin (IC50 value of 14.6 ± 1.01 µM). An in vitro nitric oxide (NO) assay was performed to select compounds for in vivo anti-inflammatory activity evaluation. SF13 scavenged the NO level to a maximum of 85% at 50 µM concentration, followed by SF1 and SF2. Based on the NO scavenging assay results, in vivo anti-inflammatory studies were also performed and the results showed significant activity compared to the standard, acetylsalicylic acid (ASA). Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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20 pages, 4351 KiB  
Article
Theoretical and Experimental Investigations of Large Stokes Shift Fluorophores Based on a Quinoline Scaffold
by Barbara Czaplińska, Katarzyna Malarz, Anna Mrozek-Wilczkiewicz, Aneta Slodek, Mateusz Korzec and Robert Musiol
Molecules 2020, 25(11), 2488; https://doi.org/10.3390/molecules25112488 - 27 May 2020
Cited by 30 | Viewed by 4514
Abstract
A series of novel styrylquinolines with the benzylidene imine moiety were synthesized and spectroscopically characterized for their applicability in cellular staining. The spectroscopic study revealed absorption in the ultraviolet–visible region (360–380 nm) and emission that covered the blue-green range of the light (above [...] Read more.
A series of novel styrylquinolines with the benzylidene imine moiety were synthesized and spectroscopically characterized for their applicability in cellular staining. The spectroscopic study revealed absorption in the ultraviolet–visible region (360–380 nm) and emission that covered the blue-green range of the light (above 500 nm). The fluorescence quantum yields were also determined, which amounted to 0.079 in the best-case scenario. The structural features that are behind these values are also discussed. An analysis of the spectroscopic properties and the theoretical calculations indicated the charge-transfer character of an emission, which was additionally evaluated using the Lippert–Mataga equation. Changes in geometry in the ground and excited states, which had a significant influence on the emission process, are also discussed. Additionally, the capability of the newly synthesized compounds for cellular staining was also investigated. These small molecules could effectively penetrate through the cellular membrane. Analyses of the images that were obtained with several of the tested styrylquinolines indicated their accumulation in organelles such as the mitochondria and the endoplasmic reticulum. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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12 pages, 2149 KiB  
Article
Antifungal Styryloquinolines as Candida albicans Efflux Pump Inhibitors: Styryloquinolines are ABC Transporter Inhibitors
by Wioleta Cieslik, Joanna Szczepaniak, Anna Krasowska and Robert Musiol
Molecules 2020, 25(2), 345; https://doi.org/10.3390/molecules25020345 - 15 Jan 2020
Cited by 15 | Viewed by 3446
Abstract
Styrylquinolines are heterocyclic compounds that are known for their antifungal and antimicrobial activity. Metal complexation through hydroxyl groups has been claimed to be a plausible mechanism of action for these types of compounds. A series of novel structures with protected hydroxyl groups have [...] Read more.
Styrylquinolines are heterocyclic compounds that are known for their antifungal and antimicrobial activity. Metal complexation through hydroxyl groups has been claimed to be a plausible mechanism of action for these types of compounds. A series of novel structures with protected hydroxyl groups have been designed and synthesized to verify the literature data. Their antifungal activity against wild-type Candida albicans strain and mutants with silenced efflux pumps activity has been determined. Combinations with fluconazole revealed synergistic interactions that were dependent on the substitution pattern. These results open a new route for designing active antifungal agents on a styrylquinoline scaffold. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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13 pages, 3251 KiB  
Article
Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent
by László Hackler, Jr., Márió Gyuris, Orsolya Huzián, Róbert Alföldi, Gábor J. Szebeni, Ramóna Madácsi, Levente Knapp, Iván Kanizsai and László G. Puskás
Molecules 2019, 24(23), 4269; https://doi.org/10.3390/molecules24234269 - 23 Nov 2019
Cited by 8 | Viewed by 3607
Abstract
Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer’s disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective [...] Read more.
Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer’s disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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40 pages, 2888 KiB  
Article
8-Hydroxyquinoline Glycoconjugates: Modifications in the Linker Structure and Their Effect on the Cytotoxicity of the Obtained Compounds
by Monika Krawczyk, Gabriela Pastuch-Gawołek, Aleksandra Pluta, Karol Erfurt, Adrian Domiński and Piotr Kurcok
Molecules 2019, 24(22), 4181; https://doi.org/10.3390/molecules24224181 - 18 Nov 2019
Cited by 23 | Viewed by 3935
Abstract
Small molecule nitrogen heterocycles are very important structures, widely used in the design of potential pharmaceuticals. Particularly, derivatives of 8-hydroxyquinoline (8-HQ) are successfully used to design promising anti-cancer agents. Conjugating 8-HQ derivatives with sugar derivatives, molecules with better bioavailability, selectivity, and solubility are [...] Read more.
Small molecule nitrogen heterocycles are very important structures, widely used in the design of potential pharmaceuticals. Particularly, derivatives of 8-hydroxyquinoline (8-HQ) are successfully used to design promising anti-cancer agents. Conjugating 8-HQ derivatives with sugar derivatives, molecules with better bioavailability, selectivity, and solubility are obtained. In this study, 8-HQ derivatives were functionalized at the 8-OH position and connected with sugar derivatives (D-glucose or D-galactose) substituted with different groups at the anomeric position, using copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC). Glycoconjugates were tested for inhibition of the proliferation of cancer cell lines (HCT 116 and MCF-7) and inhibition of β-1,4-galactosyltransferase activity, which overexpression is associated with cancer progression. All glycoconjugates in protected form have a cytotoxic effect on cancer cells in the tested concentration range. The presence of additional amide groups in the linker structure improves the activity of glycoconjugates, probably due to the ability to chelate metal ions present in many types of cancers. The study of metal complexing properties confirmed that the obtained glycoconjugates are capable of chelating copper ions, which increases their anti-cancer potential. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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Review

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21 pages, 4038 KiB  
Review
5,8-Quinolinedione Scaffold as a Promising Moiety of Bioactive Agents
by Monika Kadela-Tomanek, Ewa Bębenek, Elwira Chrobak and Stanisław Boryczka
Molecules 2019, 24(22), 4115; https://doi.org/10.3390/molecules24224115 (registering DOI) - 14 Nov 2019
Cited by 25 | Viewed by 3044
Abstract
Natural 5,8-quinolinedione antibiotics exhibit a broad spectrum of activities including anticancer, antibacterial, antifungal, and antimalarial activities. The structure–activity research showed that the 5,8-quinolinedione scaffold is responsible for its biological effect. The subject of this review report is a presentation of the pharmacological activity [...] Read more.
Natural 5,8-quinolinedione antibiotics exhibit a broad spectrum of activities including anticancer, antibacterial, antifungal, and antimalarial activities. The structure–activity research showed that the 5,8-quinolinedione scaffold is responsible for its biological effect. The subject of this review report is a presentation of the pharmacological activity of synthetic 5,8-quinolinedione compounds containing different groups at C-6 and/or C-7 positions. The relationship between the activity and the mechanism of action is included if these data have been included in the original literature. The review mostly covers the period between 2000 and 2019. Previously published literature data were used to present historical points. Full article
(This article belongs to the Special Issue Synthesis and Application of Quinolines and Quinoline Derivatives)
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