Medicinal Chemistry Research最新文献

Vascular endothelial growth factor receptor-2 (VEGFR-2), a tyrosine kinase receptor (TKR) is frequently overexpressed in most of the cancers. It plays a crucial part in tumor angiogenesis through mediating vital angiogenic cellular signals, including endothelial cell survival, proliferation, migration and vascular permeability. Due to the key importance in facilitated tumor vasculature, VEGFR-2 has emerged as a legit therapeutic target against cancer. Quinoline a fused heterocyclic scaffold with weak basicity can deliver a diverse degree of activity upon chemical substitution and attract considerable scientific attention. Quinoline containing compounds namely lenvatinib and cabozantinib have been approved as VEGFR-2 inhibitors for the management of various categories of cancer, while some drugs such as lucitanib and foretanib are currently under clinical evaluation. Some recently synthesized quinoline-(1H)-4 one derivative substituted at 3^rd, and 6^th position, and another compound substituted at 4^th position with 2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-6-amine have showed VEGFR-2 inhibition better than the standard drugs sorafenib and sunitinib, respectively (45 nM, and 40 nM, respectively). The quinoline analogs hold promise as VEGFR-2 inhibitors for future cancer treatment, with ongoing research addressing the structural refinement, potential toxicity and combination therapies. This review summarizes the role of VEGFR-2 in cancer progression, and quinoline containing compounds as VEGFR-2 inhibitors for cancer therapy.

The prevailing COVID-19 pandemic, triggered by the novel coronavirus SARS-CoV-2, stands as the predominant global health crisis of the decade, claiming millions of lives and causing profound disruptions to society. Despite the rapid development of vaccines against COVID-19, the situation remains challenging, necessitating the exploration of new antiviral drugs. In this study, we present the design and synthesis of diphenyl-1H-imidazole derivatives as a potential lead series for inhibiting the SARS-CoV-2 3CL^pro enzyme. The synthesized molecules underwent screening for inhibiting the SARS-CoV-2 3CL^pro enzyme at a concentration of 20 µM. Compounds 6–14 exhibited inhibition ranging from 88 to 99%. Further assessments were conducted to evaluate the anti-SARS-CoV-2 activity of these compounds against both the ancestral SARS-CoV-2 strain and the Delta variant in virus-infected cells. Compounds such as 4-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-1H-imidazole (9), 4-(2,4-dichlorophenyl)-2-(3,4-dimethoxyphenyl)-1H-imidazole (10), and 4-(4-(2,4-dichlorophenyl)-1H-imidazol-2-yl)benzene-1,2-diol (14) exhibited promising activity against both the SARS-CoV-2 strain (with IC₅₀ values of 7.7 µM, 12.6 µM, and 11.8 µM, respectively) and the Delta variant (with IC₅₀ values of 7.4 µM, 13.8 µM, and 12.1 µM, respectively). Moreover, the 3CL^pro inhibition IC₅₀ values for these compounds correlated well with the observed antiviral activity, measuring at 5.1 µM (9), 10.9 µM (10), and 7.3 µM (14). These findings underscore the efficacy of diphenyl-1H-imidazole derivatives as promising candidates for further development and optimization in the fight against COVID-19.

Development of resistance against most of the clinical antibiotics is a menace to mankind for their use in future. Present study aimed at design and synthesis of some microtubule dynamics modulators as antibacterial and anticancer agents. Eight diverse Aza Michael adducts were prepared at diarylpropenone core possessing desired motifs in 38–57% yields. Compound 6b showed significant antiproliferative activity against K562, leukemic cell line. While compound 6h exhibited potent antibacterial activity against methicillin resistant Staphylococcus aureus and methicillin resistant S. epidermidis. In the checkerboard experiment, 6h showed synergistic effect in combination of penicillin and also with norfloxacin, up to four-fold reduction in quantity of the antibiotic drug. Its effect was bacteriostatic as evident from time kill assay. The 3,4,5-trimethoxyphenyl motif induces antitubulin effect in Aza Michael adduct 6b for anticancer activity. Both the leads can further be optimized for better efficacy in future.

FMS-like tyrosine kinase 3 (Flt3) is an oncogenic kinase implicated in leukemia, with its primary association being acute myeloid leukemia (AML). Flt3-specific inhibitors have demonstrated promising outcomes in disrupting AML progression. While isoindigo derivatives, e.g., meisoindigo, have proven effective against chronic myeloid leukemia, their structural resemblance to indirubin derivatives, known for potent anti-Flt3 bioactivities, does not guarantee similar effects. In fact, meisoindigo and other related derivatives have been reported to exhibit limited or no anti-Flt3 bioactivities. This observation prompted us to explore the anti-Flt3 profile of novel isoindigo derivatives. Employing docking studies on both wild-type and mutated active Flt3, we synthesized a series of isoindigo derivatives and assessed their Flt3 inhibitions. Nine derivatives displayed low micromolar and submicromolar IC₅₀ values. The most potent derivative achieved an IC₅₀ of 88 nM against the mutant Flt3D835Y. Intriguingly, the same compound showed an anti-RET kinase IC₅₀ of 57 nM, reminiscent of the dual Flt3/RET inhibitory profiles of indirubin derivatives. Cell-based bioassays further revealed that these derivatives exhibited submicromolar selective toxicities against HL-60 human leukemia cells, which overexpress Flt3. In contrast, no cytotoxic effects were observed on HCT-116 colon cancer cells, MCF-7 breast cancer cells, or normal fibroblasts, all known to lack Flt3 expression.

This systematic review, which was carried out between 2018 and 2022 in accordance with PRISMA principles, assesses how machine learning (ML) and other computational approaches are integrated into drug discovery, with a focus on virtual screening (VS). The main goals are to evaluate the state of in silico drug-target interaction prediction techniques, gather useful computational tools, and provide model building help. The study emphasizes the significance of ML, molecular docking, bioinformatics, and cheminformatics in improving drug development efficiency by assessing 201 papers, of which 119 met inclusion criteria. It serves as a methodological guide for researchers, emphasizing on the effective use of computational approaches and decision-making improvements. This study relates computational techniques to drug development, discusses present constraints, and recommends future research topics with the goal of accelerating and improving therapeutic agent discovery. In summary, this systematic review highlighted numerous major tools, databases, and techniques that are critical in computational drug discovery, including the ChEMBL Database, Random Forest (RF) Algorithm, Extended Connectivity Fingerprints (ECFP), and RDKit. These tools and techniques highlight the transforming power of computational methods in pharmaceutical development. They offer researchers the ability to develop new computational models and improve drug development processes, thereby enabling the rapid advancement for new therapeutic agents via robust platforms.

A library of N-benzylbenzamide, N-phenethylbenzamide and N-benzyloxybenzamide derivatives were designed, synthesized and evaluated as amyloid beta (Aβ42) aggregation inhibitors. These compounds were designed by replacing the α,β-unsaturated linker region of chalcone with an amide bioisostere. The Aβ42 aggregation inhibition properties of these 27 benzamide derivatives were evaluated by the thioflavin T (ThT)-based fluorescence aggregation kinetics assay, transmission electron microscopy (TEM) studies, Aβ42-induced cytotoxicity assay in mouse hippocampal neuronal HT22 cell lines, fluorescence live cell imaging, and computational modelling studies using a pentamer model of Aβ42. These studies led to the identification of N-benzylbenzamides 3a and 3f, N-phenethylbenzamide 5a and N-benzyloxybenzamide 7a as promising compounds that were able to exhibit anti-aggregation properties in the ThT-based fluorescence experiments, TEM studies and more significantly were able to rescue the hippocampal neuronal HT22 cells from Aβ42-induced cytotoxicity (91–96% cell viability at 25 µM). These results demonstrate the usefulness of these benzamide-based templates in the design and development of novel small molecules as chemical tools and therapeutics to study and treat Alzheimer’s disease.