In silico and in vitro evaluation of N-heterocyclic derivatives as antimicrobials: ADMET analysis, SAR, and molecular...

N-heterocyclic derivatives frameworks are a promising axis for antimicrobial discovery, yet aligning cellular efficacy with developability remains challenging. We examined 14 derivatives to derive qualitative structure-activity trends while integrating in-silico filters. Compounds were prepared and assayed by a standardized disc-diffusion test (800 µg/disc) against Candida albicans, C. glabrata, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, enabling comparison within a matched series. Measurable inhibition zones were observed; for example, compound 5 ((1 H-1,2,4-triazol-1-yl)methanol) gave ≈ 15.2 ± 0.5 mm (C. albicans) and ≈ 19.8 ± 0.6 mm (C. glabrata), while compound 6 ((1 H-imidazol-1-yl)methanol) showed ≈ 12.8 ± 0.4 mm and ≈ 15.3 ± 0.5 mm, respectively. Bacterial effects reached > 26 mm on E. coli (compound 5) and up to 32 mm on S. aureus (compound 6), compared with ampicillin discs (≈ 14-15 mm). In parallel, molecular docking (AutoDock Vina) at mechanistically relevant targets AmpC (1KE4) and CYP51 (5TL8) yielded plausible binding poses with representative affinities in the ≈ - 6 to - 7.8 kcal mol^-1 range for several analogues, interpreted qualitatively as mechanistic context rather than rank-order predictors. Overall, this integrated approach provides mechanistic insight and hypothesis-generating SAR, guiding risk-aware prioritization for subsequent quantitative susceptibility testing and focused optimization.

The online version contains supplementary material available at 10.1007/s40203-025-00445-y.