Bioorganic and Medicinal Chemistry Reports

The rising resistance to antimicrobial drugs has highlighted the urgent need for discovering novel compounds with diverse mechanisms of action that can target both sensitive and resistant strains. To address this, we developed some chalcone analogs. In this study, a series of compounds (12-15) featuring fluoro and trifluoromethyl groups on the B ring were synthesized and evaluated for their antimicrobial properties. The positions of the substituents on the B ring were altered to assess their impact on antimicrobial activity. Compounds 13 and 14 demonstrated potent antibacterial activity (MIC = 15.6 and 7.81 μg/mL, respectively) against Staphylococcus aureus. Overall, our findings highlight Compounds 13 and 14 as promising scaffolds warranting further optimization for the development of effective antibacterial agents.

 For screening purposes, there has been interest in creating natural product scaffolds that closely resemble drug-like compounds utilizing combinatorial chemical approaches. Various screening techniques are being developed to improve the data mining and drug development campaigns' usage of natural materials. From the tissue extract of the freshwater crab Barytelphusa cunicularis, four chemicals were shown to have biological activity against both gram-positive and gram-negative bacteria, including E. coli and B. subtilis, and S. aureus. Four pathogens were used in this study: A. niger, M. furfur, A. flavus, and P. Chrysosporium. Flavus and P. Chrysosporium, but poorly against A. Niger and M. Furfur. To further the development of potential therapeutics, structure-activity relationship (SAR) analysis via a virtual screening protocol was conducted. Bioactivity assessments confirmed the compounds' efficacy against both bacterial and fungal targets. Molecular docking analyses revealed that all four organic compounds exhibit favorable absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties and bind with the protein DNA gyrase at diverse sites. In conclusion, the compounds' notable activity with DNA gyrase suggests their potential for drug design exploration.

Invasive fungal infections (IFIs) are increasing as major infectious diseases around the world, with existing medications demonstrating limited efficacy, leading to considerable morbidity and mortality due to the absence of potent antifungal agents and the emergence of serious drug resistance. In this study, a series of bisbenzazole derivatives, featuring a methyl thio linker and either 5-nitro or chloro substituent benzimidazole ring, were synthesized using straightforward and environmentally friendly reaction conditions, and characterized via 1H NMR, 13C NMR, and IR spectral analysis. All synthesized compounds screened in vitro screening for their antifungal activity against two fungal strains, namely, C. albicans and C. parapsilosis. The compounds demonstrated significant antifungal potential, particularly against C. parapsilosis. Furthermore, molecular docking was conducted to ascertain the affinities and potential binding poses of the compounds to the catalytic regions of the target proteins 14α-demethylase (CYP51) and secreted aspartic proteases (Sapps1p). Compounds 13 and 16 exhibited the highest affinity for CYP51, with docking scores of -6.785 and -6.923 kcal/mol, respectively. The compounds' ADMET properties were assessed in silico, revealing favorable physicochemical characteristics.

The strategic design of benzimidazole structures, akin to nucleotides, facilitates intricate interactions with amino acids within protein active sites. This structural scaffold, endowed with favorable pharmacokinetic profiles and lipophilic attributes, serves as a cornerstone in crafting potent pharmaceutical entities. In this study, a series of N-(1H-benzo[d]imidazol-2-yl)-substituted benzamides was meticulously synthesized and characterized through comprehensive spectroscopic analyses including IR, NMR, and elemental analysis. Leveraging the established pharmacophoric role of substituted benzimidazoles, renowned for their documented anti-proliferative properties, this study embarked on the synthesis of benzamides employing methoxy and substituted phenyl rings as key pharmacophores, known for their anticancer efficacy. Subsequent cytotoxicity evaluations using the MTT assay against MCF7 and normal mouse fibroblasts (L929) revealed compound 9 as the leading candidate, inducing significant cytotoxicity. This suggests its potential as a potent anticancer agent through apoptotic pathways. These findings highlight compound 9 as a promising molecular scaffold that requires careful optimization for the development of effective anticancer therapies.