Triazolo-Thiazolidinone Hybrids as Multi-Target Antimicrobial Agents: Synthesis, Docking, ADMET and in vitro Validation

Abstract

The present study describes one-pot cyclocondensation for the synthesis of a series of novel triazolo-thiazolidinone derivatives (MC1-MC9) as potential antimicrobial and antitubercular agents. The synthesised compounds were characterised by their IR, ¹H NMR, ¹³C NMR and mass spectral data. Molecular docking studies against DNA gyrase subunit B of Staphylococcus aureus and Escherichia coli and lanosterol 14α-demethylase (CYP51), revealed favourable binding affinities and key active-site interactions for several derivatives. ADMET predictions indicated acceptable drug-likeness, pharmacokinetic behaviour and an overall manageable toxicity profile. In vitro antimicrobial screening showed dose-dependent activity, with compounds MC2, MC3, MC7 and MC8 exhibiting prominent antibacterial effects, producing zones of inhibition up to 15-16 mm against S. aureus and E. coli at 200 µg/mL. Antifungal testing against C. albicans showed that compounds MC4 and MC8 were quite effective, with inhibition zones of 14 mm at 200 µg/mL. Antitubercular screening against Mycobacterium tuberculosis H37Rv revealed compounds MC2 and MC4 as the most effective compounds at a minimum inhibitory concentration (MIC) of 3.125 µg/mL, although compounds MC5, MC8 and MC9 had significant action at a MIC of 6.25 µg/mL. The structure–activity relationship analysis revealed that electronic substituents significantly influence biological activity, with MC2 and MC4 identified as promising candidates for further optimisation.