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Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 9643

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Dr. Mashooq Ahmad Bhat

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Guest Editor

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Interests: drug design; antimicrobial agents; molecular modelling; drug synthesis; anticancer

Dr. Ahmed M Naglah

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Guest Editor

Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Interests: drug delivery; metal drug interactions; biological activities; crystal structures
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Dear Colleagues,

The chemistry of heterocyclic compounds, especially five-membered heterocycles, has attracted numerous researchers in medicinal chemistry, biochemistry, and pharmacology. The area of medicinal chemistry fascinates researchers through the structure, synthesis, physicochemical properties, and especially biological properties of these small molecules, leading to an enormous source of active small molecules for the development of new drugs. This Special Issue of Molecules aims to stimulate new research on the synthesis and characterization of novel five-membered heterocyclic compounds. The five-membered heterocyclic compounds are synthesized by optimized synthesis methods already known or by developing new methods and to evaluate the biological activity of new small molecules to determine the efficacy and potency of novel compounds. Research output in the form of an original research article, or review on new pharmacological effects and on the structure–biological activity relationship of compounds is also expected. Although five-membered heterocyclic compounds are reported to have anti-bacterial, antifungal, anti-inflammatory, anticancer, and antioxidant activity. Other research based on the biological activity of five-membered heterocyclic compounds can also be of interest. We cordially invite authors to submit original articles and reviews that will contribute to new five-membered heterocyclic compounds with potent biological activity.

Dr. Mashooq Ahmad Bhat
Dr. Ahmed M Naglah
Guest Editors

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Keywords

drug design
synthesis
biological evaluation
antimicrobial activity
anticancer activity
molecular modeling
five membered heterocycles

Published Papers (7 papers)

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Research

22 pages, 2912 KiB

Open AccessArticle

New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study

by Mariam M. Fakhry, Amr A. Mattar, Marwa Alsulaimany, Ebtesam M. Al-Olayan, Sara T. Al-Rashood and Hatem A. Abdel-Aziz

Molecules 2023, 28(21), 7455; https://doi.org/10.3390/molecules28217455 - 6 Nov 2023

Cited by 3 | Viewed by 1345

Abstract

A new series of thiazolyl-pyrazoline derivatives (4a–d, 5a–d 6a, b, 7a–d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a–b). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC₅₀ = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC₅₀ = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC₅₀ = 0.024, and 0.005 µM, respectively, whereas their IC₅₀ = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC₅₀ = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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17 pages, 3479 KiB

Open AccessArticle

Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies

by Heba E. Hashem, Abd El-Galil E. Amr, Abdulrahman A. Almehizia, Ahmed M. Naglah, Benson M. Kariuki, Heba A. Eassa and Eman S. Nossier

Molecules 2023, 28(21), 7252; https://doi.org/10.3390/molecules28217252 - 25 Oct 2023

Cited by 2 | Viewed by 1350

Abstract

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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18 pages, 4150 KiB

Open AccessArticle

Development of a New Benzofuran–Pyrazole–Pyridine-Based Molecule for the Management of Osteoarthritis

by Somaia S. Abd El-Karim, Ahlam H. Mahmoud, Asmaa K. Al-Mokaddem, Noha E. Ibrahim, Hamad M. Alkahtani, Amer Alhaj Zen and Manal M. Anwar

Molecules 2023, 28(19), 6814; https://doi.org/10.3390/molecules28196814 - 27 Sep 2023

Cited by 1 | Viewed by 1268

Abstract

Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease’s symptoms. So, drug development for the management of osteoarthritis represents an important challenge in the medical field. This work is based on the development of a new benzofuran–pyrazole–pyridine-based compound 8 with potential anti-inflammatory and anti-osteoarthritis properties. Microanalytical and spectral data confirmed the chemical structure of compound 8. The biological assays indicated that compound 8 produces multifunctional activity as an anti-osteoarthritic candidate via inhibition of pro-inflammatory mediators, including RANTES, CRP, COMP, CK, and LPO in OA rats. Histopathological and pharmacokinetic studies confirmed the safety profile of the latter molecule. Accordingly, compound 8 is considered a promising anti-osteoarthritis agent and deserves deeper investigation in future trials. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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17 pages, 2425 KiB

Open AccessArticle

Synthesis and Anti-Inflammatory Activity of N(2)-Arylindazol-3(2H)-One Derivatives: Copper-Promoted Direct N-Arylation via Chan–Evans–Lam Coupling

by Kyungmin Kim, Jeong Ho Kim, Heejae Choi, Byeongno Lee, Jihyun Lee, Kang Min Ok, Tae Hoon Lee and Hakwon Kim

Molecules 2023, 28(18), 6706; https://doi.org/10.3390/molecules28186706 - 20 Sep 2023

Viewed by 849

Abstract

Inflammatory-related diseases are becoming increasingly prevalent, leading to a growing focus on the development of anti-inflammatory agents, with a particular emphasis on creating novel structural compounds. In this study, we present a highly efficient synthetic method for direct N-arylation to produce a variety of N(2)-arylindazol-3(2H)-ones 3, which exhibit anti-inflammatory activity. The Chan–Evans–Lam (CEL) coupling of N(1)-benzyl-indazol-3-(2H)-ones 1 with arylboronic acids 2 in the presence of a copper complex provided the corresponding N(2)-arylindazol-3(2H)-ones 3 in good-to-excellent yields, as identified with NMR, MS, and X-ray crystallography techniques. The cell viability and anti-inflammatory effects of the synthesized compounds (3 and 5) were briefly assessed using the MTT method and Griess assay. Among them, compounds 5 exhibited significant anti-inflammatory effects with negligible cell toxicity. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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23 pages, 5957 KiB

Open AccessArticle

Synthesis and In Vitro Anticancer Activity of Novel 4-Aryl-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridines Arrest Cell Cycle and Induce Cell Apoptosis by Inhibiting CDK2 and/or CDK9

by Basma S. Almansour, Faizah A. Binjubair, Alaa A.-M. Abdel-Aziz and Sara T. Al-Rashood

Molecules 2023, 28(17), 6428; https://doi.org/10.3390/molecules28176428 - 4 Sep 2023

Viewed by 1318

Abstract

Two series of pyrazolo[3,4-b]pyridine derivatives, 9a–h and 14a–h, are synthesized and evaluated for their anti-cancer potency towards Hela, MCF7, and HCT-116 cancer cell lines. Compound 9a showed the highest anticancer activity with IC₅₀ = 2.59 µM against Hela when compared with doxorubicin (IC₅₀ = 2.35 µM). Compound 14g revealed cytotoxicity IC₅₀ = 4.66 and 1.98 µM towards MCF7 and HCT-116 compared to doxorubicin with IC₅₀ = 4.57 and 2.11 µM, respectively. Compound 9a exhibited cell cycle arrest at the S phase for Hela, whereas 14g revealed an arresting cell cycle for MCF7 at G2/M phase and an arresting cell cycle at S phase in HCT-116. In addition, 9a induced a significant level of early and late apoptosis in Hela when compared with the control cells, whereas 14g induced an apoptosis in MCF7 and HCT-116, respectively. Compounds 9a (IC₅₀ = 26.44 ± 3.23 µM) and 14g (IC₅₀ = 21.81 ± 2.96 µM) showed good safety profiles on normal cell line WI-38. Compounds 9a and 14g showed good inhibition activity towards CDK2, with IC₅₀ = 1.630 ± 0.009 and 0.460 ± 0.024 µM, respectively, when compared with ribociclib (IC₅₀ = 0.068 ± 0.004). Furthermore, 9a and 14g showed inhibitory activity towards CDK9 with IC₅₀ = 0.262 ± 0.013 and 0.801 ± 0.041 µM, respectively, related to IC₅₀ of ribociclib = 0.050 ± 0.003. Docking study for 9a and 14g exhibited good fitting in the CDK2 and CDK9 active sites. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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17 pages, 4168 KiB

Open AccessArticle

Unfolding the Antibacterial Activity and Acetylcholinesterase Inhibition Potential of Benzofuran-Triazole Hybrids: Synthesis, Antibacterial, Acetylcholinesterase Inhibition, and Molecular Docking Studies

by Sadaf Saeed, Ameer Fawad Zahoor, Shagufta Kamal, Zohaib Raza and Mashooq Ahmad Bhat

Molecules 2023, 28(16), 6007; https://doi.org/10.3390/molecules28166007 - 10 Aug 2023

Cited by 2 | Viewed by 1029

Abstract

In this study, a series of novel benzofuran-based 1,2,4-triazole derivatives (10a–e) were synthesized and evaluated for their inhibitory potential against acetylcholinesterase (AChE) and bacterial strains (E. coli and B. subtilis). Preliminary results revealed that almost all assayed compounds displayed promising efficacy against AChE, while compound 10d was found to be a highly potent inhibitor of AChE. Similarly, these 5-bromobenzofuran-triazoles 10a–e were screened against B. subtilis QB-928 and E. coli AB-274 to evaluate their antibacterial potential in comparison to the standard antibacterial drug penicillin. Compound 10b was found to be the most active among all screened scaffolds, with an MIC value of 1.25 ± 0.60 µg/mL against B. subtilis, having comparable therapeutic efficacy to the standard drug penicillin (1 ± 1.50 µg/mL). Compound 10a displayed excellent antibacterial therapeutic efficacy against the E. coli strain with comparable MIC of 1.80 ± 0.25 µg/mL to that of the commercial drug penicillin (2.4 ± 1.00 µg/mL). Both the benzofuran-triazole molecules 10a and 10b showed a larger zone of inhibition. Moreover, IFD simulation highlighted compound 10d as a novel lead anticholinesterase scaffold conforming to block entrance, limiting the swinging gate, and disrupting the catalytic triad of AChE, and further supported its significant AChE inhibition with an IC₅₀ value of 0.55 ± 1.00 µM. Therefore, compound 10d might be a promising candidate for further development in Alzheimer’s disease treatment, and compounds 10a and 10b may be lead antibacterial agents. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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19 pages, 3760 KiB

Open AccessArticle

New Indazol-Pyrimidine-Based Derivatives as Selective Anticancer Agents: Design, Synthesis, and In Silico Studies

by Hanaa M. Al-Tuwaijri, Ebtehal S. Al-Abdullah, Ahmed A. El-Rashedy, Siddique Akber Ansari, Aliyah Almomen, Hanan M. Alshibl, Mogedda E. Haiba and Hamad M. Alkahtani

Molecules 2023, 28(9), 3664; https://doi.org/10.3390/molecules28093664 - 23 Apr 2023

Cited by 4 | Viewed by 1584

Abstract

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds—4f, 4i, 4a, 4g, and 4d—possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC₅₀ values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC₅₀ value of 8.029 μM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein–ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski’s rule of five and Veber’s rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents. Full article

(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Five Membered Heterocycles)

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