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

Abstract

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, including1H and13C 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 N-substituted 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 TRP-353 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 IC<inf>50</inf> value of 34.8 μM 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. © 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.