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Heterocyclic Compounds in Medicinal Chemistry

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

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 24214

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Special Issue Editors

Dr. Valentina Noemi Madia

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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: drug design and synthesis; medicinal chemistry; organic synthesis; antimicrobial agents; structure–activity relationship; antiviral agents; antiparasitic agents; anticancer agents; antiprotozoal agents
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Dr. Davide Ialongo

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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 Issues, Collections and Topics in MDPI journals

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

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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

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32 pages, 2979 KiB

Open AccessArticle

Synthesis, Absolute Configuration, Biological Profile and Antiproliferative Activity of New 3,5-Disubstituted Hydantoins

by Mladenka Jurin, Ana Čikoš, Višnja Stepanić, Marcin Górecki, Gennaro Pescitelli, Darko Kontrec, Andreja Jakas, Tonko Dražić and Marin Roje

Pharmaceuticals 2024, 17(10), 1259; https://doi.org/10.3390/ph17101259 - 24 Sep 2024

Viewed by 989

Abstract

Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives 5a–i were prepared as racemic mixtures of syn- and anti-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of syn-5a and anti-hydantoins 5b were separated by preparative high-performance liquid chromatography (HPLC) using n-hexane/2-propanol (90/10, v/v) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers 5a was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated in vitro against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound anti-5c showed potent cytotoxic activity against the human tumor cell line MCF7 (IC₅₀ = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC₅₀ = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)

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20 pages, 4294 KiB

Open AccessArticle

In Silico Exploration of Novel EGFR Kinase Mutant-Selective Inhibitors Using a Hybrid Computational Approach

by Md Ali Asif Noor, Md Mazedul Haq, Md Arifur Rahman Chowdhury, Hilal Tayara, HyunJoo Shim and Kil To Chong

Pharmaceuticals 2024, 17(9), 1107; https://doi.org/10.3390/ph17091107 - 23 Aug 2024

Viewed by 1679

Abstract

Targeting epidermal growth factor receptor (EGFR) mutants is a promising strategy for treating non-small cell lung cancer (NSCLC). This study focused on the computational identification and characterization of potential EGFR mutant-selective inhibitors using pharmacophore design and validation by deep learning, virtual screening, ADMET (Absorption, distribution, metabolism, excretion and toxicity), and molecular docking-dynamics simulations. A pharmacophore model was generated using Pharmit based on the potent inhibitor JBJ-125, which targets the mutant EGFR (PDB 5D41) and is used for the virtual screening of the Zinc database. In total, 16 hits were retrieved from 13,127,550 molecules and 122,276,899 conformers. The pharmacophore model was validated via DeepCoy, generating 100 inactive decoy structures for each active molecule and ADMET tests were conducted using SWISS ADME and PROTOX 3.0. Filtered compounds underwent molecular docking studies using Glide, revealing promising interactions with the EGFR allosteric site along with better docking scores. Molecular dynamics (MD) simulations confirmed the stability of the docked conformations. These results bring out five novel compounds that can be evaluated as single agents or in combination with existing therapies, holding promise for treating the EGFR-mutant NSCLC. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)

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18 pages, 2952 KiB

Open AccessArticle

Discovery of 1H-benzo[d]imidazole-(halogenated) Benzylidenebenzohydrazide Hybrids as Potential Multi-Kinase Inhibitors

by Tebyan O. Mirgany, Hanadi H. Asiri, A. F. M. Motiur Rahman and Mohammed M. Alanazi

Pharmaceuticals 2024, 17(7), 839; https://doi.org/10.3390/ph17070839 - 26 Jun 2024

Viewed by 1226

Abstract

In an effort to develop improved and effective targeted tyrosine kinase inhibitors (TKIs), a series of twelve novel compounds with the structural motif “(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-N

^{'}

-(halogenated)benzylidenebenzohydrazide” were successfully synthesized in three steps, yielding high product yields [...] Read more.

^{'}

-(halogenated)benzylidenebenzohydrazide” were successfully synthesized in three steps, yielding high product yields (53–97%). Among this new class of compounds, 6c and 6h-j exhibited excellent cytotoxic effects against four different cancer cell lines, with half-maximal inhibitory concentration (IC₅₀) values ranging from 7.82 to 21.48

μ

M. Notably, compounds 6h and 6i emerged as the most potent inhibitors, demonstrating significant activity against key kinases such as EGFR, HER2, and CDK2. Furthermore, compound 6h displayed potent inhibitory activity against AURKC, while 6i showed potent inhibitory effects against the mTOR enzyme, with excellent IC₅₀ values comparable with well-established TKIs. The mechanistic study of lead compound 6i revealed its ability to induce cell cycle arrest and apoptosis in HepG2 liver cancer cells. This was accompanied by upregulation of pro-apoptotic caspase-3 and Bax and downregulation of anti-apoptotic Bcl-2. Additionally, molecular docking studies indicated that the binding interactions of compounds 6h and 6i with the target enzymes give multiple interactions. These results underscore the ability of compound 6i as a compelling lead candidate warranting further optimization and development as a potent multi-targeted kinase inhibitor, which could have significant implications for the treatment of various cancers. The detailed structural optimization, mechanism of action, and in vivo evaluation of this class of compounds warrant further investigation to assess their therapeutic potential. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)

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22 pages, 2178 KiB

Open AccessArticle

Study of the Lipophilicity and ADMET Parameters of New Anticancer Diquinothiazines with Pharmacophore Substituents

by Daria Klimoszek, Małgorzata Jeleń, Małgorzata Dołowy and Beata Morak-Młodawska

Pharmaceuticals 2024, 17(6), 725; https://doi.org/10.3390/ph17060725 - 3 Jun 2024

Cited by 3 | Viewed by 863

Abstract

Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as R_M0, was determined experimentally by the RP-TLC method using RP18 plates and acetone–TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (R_M0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)

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41 pages, 9942 KiB

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Unveiling the Multifaceted Capabilities of Endophytic Aspergillus flavus Isolated from Annona squamosa Fruit Peels against Staphylococcus Isolates and HCoV 229E—In Vitro and In Silico Investigations

by Noha Fathallah, Wafaa M. Elkady, Sara A. Zahran, Khaled M. Darwish, Sameh S. Elhady and Yasmin A. Elkhawas

Pharmaceuticals 2024, 17(5), 656; https://doi.org/10.3390/ph17050656 - 19 May 2024

Viewed by 1927

Abstract

Recently, there has been a surge towards searching for primitive treatment strategies to discover novel therapeutic approaches against multi-drug-resistant pathogens. Endophytes are considered unexplored yet perpetual sources of several secondary metabolites with therapeutic significance. This study aims to isolate and identify the endophytic fungi from Annona squamosa L. fruit peels using morphological, microscopical, and transcribed spacer (ITS-rDNA) sequence analysis; extract the fungus’s secondary metabolites by ethyl acetate; investigate the chemical profile using UPLC/MS; and evaluate the potential antibacterial, antibiofilm, and antiviral activities. An endophytic fungus was isolated and identified as Aspergillus flavus L. from the fruit peels. The UPLC/MS revealed seven compounds with various chemical classes. The antimicrobial activity of the fungal ethyl acetate extract (FEA) was investigated against different Gram-positive and Gram-negative standard strains, in addition to resistant clinical isolates using the agar diffusion method. The CPE-inhibition assay was used to identify the potential antiviral activity of the crude fungal extract against low pathogenic human coronavirus (HCoV 229E). Selective Gram-positive antibacterial and antibiofilm activities were evident, demonstrating pronounced efficacy against both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA). However, the extract exhibited very weak activity against Gram-negative bacterial strains. The ethyl acetate extract of Aspergillus flavus L exhibited an interesting antiviral activity with a half maximal inhibitory concentration (IC₅₀) value of 27.2 µg/mL against HCoV 229E. Furthermore, in silico virtual molecular docking-coupled dynamics simulation highlighted the promising affinity of the identified metabolite, orienting towards three MRSA biotargets and HCoV 229E main protease as compared to reported reference inhibitors/substrates. Finally, ADME analysis was conducted to evaluate the potential oral bioavailability of the identified metabolites. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)

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27 pages, 14889 KiB

Open AccessArticle

Anticancer Evaluation of Novel Benzofuran–Indole Hybrids as Epidermal Growth Factor Receptor Inhibitors against Non-Small-Cell Lung Cancer Cells

by Yechan Lee, Sunhee Lee, Younho Lee, Doona Song, So-Hyeon Park, Jieun Kim, Wan Namkung and Ikyon Kim

Pharmaceuticals 2024, 17(2), 231; https://doi.org/10.3390/ph17020231 - 9 Feb 2024

Cited by 1 | Viewed by 1639

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 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

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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

by Eid E. Salama, Mohamed F. Youssef, Ahmed Aboelmagd, Ahmed T. A. Boraei, Mohamed S. Nafie, Matti Haukka, Assem Barakat and Ahmed A. M. Sarhan

Pharmaceuticals 2023, 16(12), 1724; https://doi.org/10.3390/ph16121724 - 13 Dec 2023

Viewed by 1579

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 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

Open AccessArticle

Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation

by Kiran Shahzadi, Syed Majid Bukhari, Asma Zaidi, Tanveer A. Wani, Muhammad Saeed Jan, Seema Zargar, Umer Rashid, Umar Farooq, Aneela Khushal and Sara Khan

Pharmaceuticals 2023, 16(11), 1552; https://doi.org/10.3390/ph16111552 - 2 Nov 2023

Cited by 5 | Viewed by 1536

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 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 ∆G_bind (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

Open AccessArticle

Synthesis, DFT Study, and In Vitro Evaluation of Antioxidant Properties and Cytotoxic and Cytoprotective Effects of New Hydrazones on SH-SY5Y Neuroblastoma Cell Lines

by Diana Tzankova, Hristina Kuteva, Emilio Mateev, Denitsa Stefanova, Alime Dzhemadan, Yordan Yordanov, Alexandrina Mateeva, Virginia Tzankova, Magdalena Kondeva-Burdina, Alexander Zlatkov and Maya Georgieva

Pharmaceuticals 2023, 16(9), 1198; https://doi.org/10.3390/ph16091198 - 23 Aug 2023

Cited by 4 | Viewed by 1264

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) 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

Open AccessArticle

New Imadazopyrazines with CDK9 Inhibitory Activity as Anticancer and Antiviral: Synthesis, In Silico, and In Vitro Evaluation Approaches

by Aisha A. Alsfouk, Hanan M. Alshibl, Najla A. Altwaijry, Ashwag Alanazi, Omkulthom AlKamaly, Ahlam Sultan and Bshra A. Alsfouk

Pharmaceuticals 2023, 16(7), 1018; https://doi.org/10.3390/ph16071018 - 18 Jul 2023

Cited by 4 | Viewed by 1524

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, 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

Open AccessReview

Recent Advances in Pyrimidine-Based Drugs

by Baskar Nammalwar and Richard A. Bunce

Pharmaceuticals 2024, 17(1), 104; https://doi.org/10.3390/ph17010104 - 11 Jan 2024

Cited by 11 | Viewed by 5909

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, 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

Open AccessReview

Synthesis and Biological Studies of Benzo[b]furan Derivatives: A Review from 2011 to 2022

by Lizeth Arce-Ramos, Juan-Carlos Castillo and Diana Becerra

Pharmaceuticals 2023, 16(9), 1265; https://doi.org/10.3390/ph16091265 - 6 Sep 2023

Cited by 11 | Viewed by 2337

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]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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