Efficient synthesis, dual anti-tubercular and antioxidant activity of triazole-acetophenone derivatives: enhanced efficacy via esterification and quantum mechanical validation of CYP121 binding

Abstract

A series of twelve novel triazole-based acetophenone derivatives (3a–3f and 4a–4f) was efficiently synthesized via a catalyst-free 1,3-dipolar cycloaddition reaction, integrating a known CYP121 inhibiting scaffold with dual anti-tubercular and antioxidant properties. The anti-tubercular screening demonstrated that the ethyl ester derivatives (series 4) possessed significantly superior activity compared to their carboxylic acid counterparts (series 3). Specifically, compounds 4b, 4d, and 4e exhibited the highest potential, with MIC values (2.60 ± 1.12 to 3.25 ± 1.12 µg mL⁻¹) nearly comparable to rifampicin (1.62 ± 0.56 µg mL⁻¹). All derivatives also displayed moderate to excellent DPPH and hydroxyl radical scavenging activity, alongside minimal cytotoxicity toward human red blood cells. Comprehensive molecular docking against the MTB CYP121 enzyme established that this enhanced efficacy was due to a shift from polar carboxylate contacts to favorable non-polar interactions, including halogen bonding and π-stacking, especially in the fluorine and trifluoromethyl-substituted esters. This differential binding pattern was further validated and characterized at the electronic level using quantum mechanics (QM) based IGMplot analysis. The findings underscore that optimal anti-tubercular efficacy requires a synergistic balance of binding affinity, substituent nature, and physicochemical properties like predicted aqueous solubility.