Harnessing N-substituted benzotriazole scaffolds as potent methionine aminopeptidase inhibitors: from chemical design to cellular efficacy

초록

Herein, we present the synthesis, characterization, and biological evaluation of twenty-five N-substituted benzotriazole derivatives as potential anticancer agents targeting methionine aminopeptidase (MAP) enzymes. The compounds were synthesized following a conventional procedure and characterized by spectroscopic techniques, including 1H and 13C NMR, FT-IR, and LCMS, for structural endorsement. Molecular docking and dynamics simulations over 100 ns revealed strong binding affinities and stable complex formation between several Nsubstituted benzotriazole derivatives and MAP type-I, outperforming the reference anticancer drugs in key protein-ligand interactions. Additionally, the compound 4g showed the highest Mechanics Poisson-Boltzmann Surface Area (MMPBSA) energy of -12.53 +/- 4.3 kcal/mol, with a major contribution from TYR-196 and TRP353 amino acid residues. Pharmacokinetic profiling using ADMET tools showed that most compounds possessed favorable drug-like properties, suitable absorption, and low toxicity. Biological assays demonstrated significant cytotoxicity, with an IC50 value of 34.8 mu M for 4g. The relative apoptotic rates of HeLa cancer cell lines using selected derivatives against the control showed notable therapeutic outcomes for 4g, 6d, and 6f. In summary, this integrated approach highlights N-substituted benzotriazole scaffolds as promising modular precursors for the development of targeted anticancer therapies focused on metabolic enzyme inhibition.

키워드