Future Medicinal Chemistry

Quinazolinones, a prominent class of heterocyclic compounds, have garnered significant attention due to their diverse biological activities and synthetic versatility. Over the past thirty years, extensive research has been conducted to explore their pharmacological potential, making them an essential scaffold in modern medicinal chemistry. This review provides an analysis of the most common synthesis methods employed for the preparation of quinazolinones, highlighting their efficiency and applicability. Furthermore, it presents an in-depth discussion of their broad-spectrum biological activities, including anticancer, antimicrobial, antifungal, anti-inflammatory, anticonvulsant, anti-Alzheimer’s, antiparasitic, antioxidant, antidiabetic, and antiviral properties. By summarizing the latest advancements in quinazolinone research, specifically those made in the past five years, this review aims to serve as a valuable resource for researchers, facilitating easy access to recent studies and promoting further advancements in the field.

Aim: Cancer is the second leading cause of death and chemotherapy is widely used and well-known for treating cancer, yet it has lots of adverse side effects, making the search for novel compounds imperative. We reported here design, synthesis, DFT analysis, anticancer evaluation and in-silico studies of new 1,3,4-oxadiazoles (4a-e). Material and methods: IMC-038525 and IMC-094332 tubulin inhibitors' oxadiazole-linked aryl cores inspired the innovative compounds, and synthesis was accomplished in two steps followed by their characterization by spectral data. The HOMO and LUMO energy gap (∆E) was determined to investigate compounds’ (4a-e) stability followed by their anticancer activity at 10 µM and in-silico studies. Results and conclusion: 5-(4-Nitrophenyl)-N-(naphthalene-2-yl)-1,3,4-oxadiazol-2-amine (4b) demonstrated substantial anticancer activity against a few cell lines like SR, MDA-MB-435, MOLT-4, K-562, and HL-60(TB). 5-(3,4,5-Trimethoxyphenyl)-N-(naphthalene-2-yl)-1,3,4-oxadiazol-2-amine (4e) demonstrated promising anticancer activity against cell lines, UO-31, NCI-H226, CAKI-1, PC-3, and MCF7. The molecular docking against tubulin's colchicine binding site (PDB ID: 1AS0), displayed a docking score of −7.295 Kcal/mol and a H-bond interaction with Ala317 residue for the ligand 4e. The ligand 4e was found to interacted 24 amino acids of the tubulin protein in MD simulation investigation with moderate local conformational changes with ligand 4e (˂ 1 Å).

Background: Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity. Methods: The synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions. Results: Among the tested compounds, 13b exhibited potent anti-proliferative activity (IC50: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC50: 41.51 nM), surpassing sorafenib (IC50: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions. Conclusion: Thiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.

Aims: This study focuses on the design and evaluation of bis-chalcones and bis-pyrimidines as potential urease inhibitors. Materials and methods: A series of bis-chalcone and bis-pyrimidine derivatives were synthesized and assessed for their in vitro urease inhibitory activity. Kinetic studies were conducted using Lineweaver-Burk plots to determine the inhibition mechanism of the most potent compound. Molecular docking was employed to investigate the binding interactions with the urease active site, followed by MD simulations to validate complex stability. Computational ADMET analysis was performed to assess the drug-like properties of the most active inhibitor. Results: Several synthesized compounds exhibited potent urease inhibitory activity, significantly surpassing the standard inhibitor thiourea. The most active compound, 8P, displayed noncompetitive inhibition, as confirmed by kinetic studies. SAR analysis revealed that electron-withdrawing substituents enhanced inhibitory potency. Molecular docking studies demonstrated favorable interactions between inhibitors and key urease residues, while MD simulations confirmed complex stability. ADMET analysis supported the drug-like potential of 8P. Conclusions: This study provides valuable insights into the development of target compounds as promising urease inhibitors. These findings suggest their potential therapeutic applications for urease-related disorders.

Aim: The purpose is to synthesize a new class of furan-based chalcone compounds (KD1-KD14) and to investigate their monoamine oxidase (MAO)-A and -B inhibitory activities. Material and method: The 14 chalcones were synthesized using an open mortar and pestle. Lead molecules were screened via inhibitory activity, BBB permeability, and computation studies. Results: Most of the tested compounds showed promising activity for MAO-B over than MAO-A. Among the molecules, KD1 and KD9 revealed the significant inhibitory potentials toward MAO-B with IC50 values of 0.023 ± 0.004 and 0.015 ± 0.001 µM, respectively, and with high selectivity indices of 723.04 and >2666.66, respectively, over MAO-A. Further, kinetics and reversibility test revealed that both KD1 and KD9 were competitive reversible MAO-B inhibitors with Ki values of 13.5 ± 4.95 and 6.15 ± 0.92 nM, respectively. Additionally, the PAMPA test showed that both KD1 and KD9 compounds permeated the central nervous system. Furthermore, molecular docking and dynamics simulations showed that both the chemicals formed pi-cation and hydrogen bonds with the MAO-B pocket and stabilized the MAO-B over the course of a 100 ns simulation. Conclusion: Our results revealed that KD1 and KD9 are potent selective, reversible, and competitive MAO-B inhibitors.