Heterocyclic Compounds in Medicinal Chemistry

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 6992

Special Issue Editors

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy
Interests: drug design and synthesis; medicinal chemistry; organic synthesis; antimicrobial agents; structure–activity relationship; antiviral agents; antiparasitic agents; anticancer agents; antiprotozoal agents
Special Issues, Collections and Topics in MDPI journals
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy
Interests: synthesis of heterocycles; medicinal chemistry; organic chemistry; medicinal chemistry and drug design; medicinal chemistry CNS drug discovery and delivery

Special Issue Information

Dear Colleagues,

The development of new medicinal agents is pivotal for the maintenance of a high quality of life as well as a healthy and productive society. Heterocycles play a key role in the biological activity of many small molecule drugs due to their capability of forming hydrogen bond, altering the polarity and modulating lipophilicity at specific sites in the pathogen or host with the overall effect of inhibiting the biological processes that lead to the progression of diseases. Indeed, most of the organic compounds used as therapeutics or intermediates utilized for their synthesis contain heterocyclic motifs that can improve pharmacological, pharmacokinetic, toxicological and physicochemical properties of compounds, making them more effective as therapeutic agents. heterocycles endowed with any biological action. Contributions that highlight the importance of heterocycles that are widely found in: agrochemicals, dyes, cosmetics and functional materials are also welcome. The aim of the present Special Issue is Heterocycle is a ring with at least one atom that is not carbon. Nitrogen, oxygen, and sulfur are the primary elements seen in common heterocycles, which play a critical role in drug discovery. Based on the size of the ring, there are three, four, five, six, seven or more membered rings, as well as fused, bicyclic and macrocyclic heterocycles. Furthermore, they are grouped as aromatic, saturated or unsaturated. Depending on the structure and on the type of bonds, such compounds show different acid-base properties and they can contain one, two or more heteroatoms.

This Special Issue will acknowledge research papers with topics including, but not limited to, the preparation of aromatic and non-aromatic also an overview primarily of the state of the art of synthetic methods and recent advances in the synthesis of heterocycles.

Dr. Valentina Noemi Madia
Dr. Davide Ialongo
Guest Editors

Manuscript Submission Information

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Keywords

  • heterocycles
  • bioactive compounds
  • drug design and discovery
  • in silico studies
  • phytochemicals
  • anticancer agents
  • antifungal agents
  • anti-inflammatory agents
  • antimicrobial agents
  • antiviral agents

Published Papers (7 papers)

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Research

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27 pages, 14889 KiB  
Article
Anticancer Evaluation of Novel Benzofuran–Indole Hybrids as Epidermal Growth Factor Receptor Inhibitors against Non-Small-Cell Lung Cancer Cells
Pharmaceuticals 2024, 17(2), 231; https://doi.org/10.3390/ph17020231 - 09 Feb 2024
Viewed by 543
Abstract
The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized [...] Read more.
The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran–indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran–indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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16 pages, 3490 KiB  
Article
Discovery of Potent Indolyl-Hydrazones as Kinase Inhibitors for Breast Cancer: Synthesis, X-ray Single-Crystal Analysis, and In Vitro and In Vivo Anti-Cancer Activity Evaluation
Pharmaceuticals 2023, 16(12), 1724; https://doi.org/10.3390/ph16121724 - 13 Dec 2023
Viewed by 834
Abstract
According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer [...] Read more.
According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer statistics continues to rise, it is imperative to explore new avenues in the ongoing battle against this disease. Therefore, a number of new indolyl-hydrazones were synthesized by reacting the ethyl 3-formyl-1H-indole-2-carboxylate 1 with thiosemicarbazide, semicarbazide.HCl, 4-nitrophenyl hydrazine, 2,4-dinitrophenyl hydrazine, and 4-amino-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione to afford the new hit compounds, which were assigned chemical structures as thiosemicarbazone 3, bis(hydrazine derivative) 5, semicarbzone 6, Schiff base 8, and the corresponding hydrazones 10 and 12 by NMR, elemental analysis, and X-ray single-crystal analysis. The MTT assay was employed to investigate the compounds’ cytotoxicity against breast cancer cells (MCF-7). Cytotoxicity results disclosed potent IC50 values against MCF-7, especially compounds 5, 8, and 12, with IC50 values of 2.73 ± 0.14, 4.38 ± 0.23, and 7.03 ± 0.37 μM, respectively, compared to staurosproine (IC50 = 8.32 ± 0.43 μM). Consequently, the activities of compounds 5, 8, and 12 in relation to cell migration were investigated using the wound-healing test. The findings revealed notable wound-healing efficacy, with respective percentages of wound closure measured at 48.8%, 60.7%, and 51.8%. The impact of the hit compounds on cell proliferation was assessed by examining their apoptosis-inducing properties. Intriguingly, compound 5 exhibited a significant enhancement in cell death within MCF-7 cells, registering a notable increase of 39.26% in comparison to the untreated control group, which demonstrated only 1.27% cell death. Furthermore, the mechanism of action of compound 5 was scrutinized through testing against kinase receptors. The results revealed significant kinase inhibition, particularly against PI3K-α, PI3K-β, PI3K-δ, CDK2, AKT-1, and EGFR, showcasing promising activity, compared to standard drugs targeting these receptors. In the conclusive phase, through in vivo assay, compound 5 demonstrated a substantial reduction in tumor volume, decreasing from 106 mm³ in the untreated control to 56.4 mm³. Moreover, it significantly attenuated tumor proliferation by 46.9%. In view of these findings, the identified leads exhibit promises for potential development into future medications for the treatment of breast cancer, as they effectively hinder both cell migration and proliferation. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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20 pages, 4898 KiB  
Article
Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation
Pharmaceuticals 2023, 16(11), 1552; https://doi.org/10.3390/ph16111552 - 02 Nov 2023
Viewed by 743
Abstract
The presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The [...] Read more.
The presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The involvement of urease in stone formation makes it a good target for finding urease enzyme inhibitors, which have the potential to be developed as lead drugs against kidney stones in the future. The documented ethnopharmacology of coumarin 2-one against bacterial, fungal and viral strains encouraged us to synthesize new derivatives of coumarins by reacting aromatic aldehydes with 4-aminocoumarin. The synthesized compounds (2a to 11a) were evaluated for their antimicrobial, in vitro, and in silico properties against the urease enzyme. The study also covers in vivo determination of the synthesized compounds with respect to different types of induced ulcers. The molecular docking study along with extended MD simulations (100 ns each) and MMPBSA study confirmed the potential inhibitory candidates as evident from computed ∆Gbind (3a = −11.62 and 5a = −12.08 Kcal/mol) against the urease enzyme. The in silico analyses were augmented by an enzymatic assay, which revealed that compounds 3a and 5a had strong inhibitory action, with IC50 of 0.412 µM (64.0% inhibition) and 0.322 µM (77.7% inhibition), respectively, compared to standard (Thiourea) with 82% inhibition at 0.14 µM. Moreover, the most active compound, 5a, was further tested in vivo for antiulcer activity by different types of induced ulcers, including pyloric ligation-, ethanol-, aspirin-, and histamine-induced ulcers. Compound 5a effectively reduced gastric acidity, lipid peroxidation, and ulceration in a rat model while also inhibiting gastric ATPase activity, which makes it a promising candidate for ulcer treatment. As a result of the current research, 3a and 5a may be used as new molecules for developing potent urease inhibitors. Additionally, the compound 3a showed antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, with zones of inhibition of 41 ± 0.9 mm and 35 ± 0.9 mm, respectively. Compound 7a showed antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, with zones of inhibition of 30 ± 0.8 mm and 42 ± 0.8 mm, respectively. These results prove that the synthesized compounds also possess good antibacterial potential against Gram-positive and Gram-negative bacterial strains. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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20 pages, 3184 KiB  
Article
Synthesis, DFT Study, and In Vitro Evaluation of Antioxidant Properties and Cytotoxic and Cytoprotective Effects of New Hydrazones on SH-SY5Y Neuroblastoma Cell Lines
Pharmaceuticals 2023, 16(9), 1198; https://doi.org/10.3390/ph16091198 - 23 Aug 2023
Viewed by 742
Abstract
A series of ten new hydrazide–hydrazone derivatives bearing a pyrrole ring were synthesized and structurally elucidated through appropriate spectral characteristics. The target hydrazones were assessed for radical scavenging activity through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests, with ethyl 5-(4-bromophenyl)-1-(2-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazine-yl)-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (7d) [...] Read more.
A series of ten new hydrazide–hydrazone derivatives bearing a pyrrole ring were synthesized and structurally elucidated through appropriate spectral characteristics. The target hydrazones were assessed for radical scavenging activity through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests, with ethyl 5-(4-bromophenyl)-1-(2-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazine-yl)-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (7d) and ethyl 5-(4-bromophenyl)-1-(3-(2-(4-hydroxy-3,5-dimethoxybenzylidene) hydra zine-yl)-3-oxopropyl)-2-methyl-1H-pyrrole-3-carboxylate (8d) highlighted as the best radical scavengers from the series. Additional density functional theory (DFT) studies have indicated that the best radical scavenging ligands in the newly synthesized molecules are stable, do not decompose into elements, are less polarizable, and with a hard nature. The energy of the highest occupied molecular orbital (HOMO) revealed that both compounds possess good electron donation capacities. Overall, 7d and 8d can readily scavenge free radicals in biological systems via the donation of hydrogen atoms and single electron transfer. The performed in vitro assessment of the compound’s protective activity on the H2O2-induced oxidative stress model on human neuroblastoma cell line SH-SY5Y determined 7d as the most perspective representative with the lowest cellular toxicity and the highest protection. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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17 pages, 4279 KiB  
Article
New Imadazopyrazines with CDK9 Inhibitory Activity as Anticancer and Antiviral: Synthesis, In Silico, and In Vitro Evaluation Approaches
Pharmaceuticals 2023, 16(7), 1018; https://doi.org/10.3390/ph16071018 - 18 Jul 2023
Viewed by 997
Abstract
This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, [...] Read more.
This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound 1d exhibited the highest CDK9 inhibition with an IC50 of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC50 values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound 4a showed the highest antiviral potency with an IC50 of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that 4a displayed a good affinity to proteases. The result of the docking studies of 4a with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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Review

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50 pages, 11795 KiB  
Review
Recent Advances in Pyrimidine-Based Drugs
Pharmaceuticals 2024, 17(1), 104; https://doi.org/10.3390/ph17010104 - 11 Jan 2024
Viewed by 1357
Abstract
Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas in which pyrimidines have had a major impact in drug discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, [...] Read more.
Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas in which pyrimidines have had a major impact in drug discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, and diabetes mellitus. The article presents the synthesis of the medicinal agents and highlights the role of the biological target with respect to the disease model. Additionally, the biological potency, ADME properties and pharmacokinetics/pharmacodynamics (if available) are discussed. This survey attempts to demonstrate the versatility of pyrimidine-based drugs, not only for their potency and affinity but also for the improved medicinal chemistry properties of pyrimidine as a bioisostere for phenyl and other aromatic π systems. It is hoped that this article will provide insight to researchers considering the pyrimidine scaffold as a chemotype in future drug candidates in order to counteract medical conditions previously deemed untreatable. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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94 pages, 30427 KiB  
Review
Synthesis and Biological Studies of Benzo[b]furan Derivatives: A Review from 2011 to 2022
Pharmaceuticals 2023, 16(9), 1265; https://doi.org/10.3390/ph16091265 - 06 Sep 2023
Cited by 3 | Viewed by 996
Abstract
The importance of the benzo[b]furan motif becomes evident in the remarkable results of numerous biological investigations, establishing its potential as a robust therapeutic option. This review presents an overview of the synthesis of and exhaustive biological studies conducted on benzo[b [...] Read more.
The importance of the benzo[b]furan motif becomes evident in the remarkable results of numerous biological investigations, establishing its potential as a robust therapeutic option. This review presents an overview of the synthesis of and exhaustive biological studies conducted on benzo[b]furan derivatives from 2011 to 2022, accentuating their exceptional promise as anticancer, antibacterial, and antifungal agents. Initially, the discussion focuses on chemical synthesis, molecular docking simulations, and both in vitro and in vivo studies. Additionally, we provide an analysis of the intricate interplay between structure and activity, thereby facilitating comparisons and profoundly emphasizing the applications of the benzo[b]furan motif within the realms of drug discovery and medicinal chemistry. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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