Design, synthesis, and antimicrobial evaluation of new triazole-tethered tetrazole hybrids via DNA gyrase inhibition

To address the increasing Antimicrobial Resistance (AMR), we developed a library of triazole-tethered tetrazole derivatives using a multicomponent synthetic click chemistry strategy. It is well known that combining two or more types of pharmacophores into one molecule could afford a new entity with varied bioactivities. Considering this, the final products (6a–6o) were synthesized in excellent yields and were duly characterized using spectrometric analysis, including NMR and HRMS. To rationalize their biological attributes, synthetics were tested using different pathogenic microbial strains (S. aureus (ATCC 25923), S. epidermidis (ATCC 35984), E. coli (ATCC 25922), A. hydrophila (ATCC 7966), P. aeruginosa (ATCC 27853), S. typhi (Clinical isolate), S. typhimurium (Clinical isolate)). The antimicrobial potential (MIC µg/mL) of compounds compared to positive control ciprofloxacin revealed that compounds 6a, 6b, 6c, 6d, 6e, 6g, 6h, 6j, 6l, and 6m exhibited significant antibacterial activity with MIC 1.56-3.12 µg/mL in vitro compared to the ciprofloxacin against Gram-positive and Gram-negative bacterial strains. The molecules were further corroborated rationally using molecular modelling and dynamics analysis to assess their binding affinity with DNA gyrase. The study established that 6g and 6e possess a high affinity within the gyrase, as revealed by molecular docking analysis compared to ciprofloxacin. The molecular dynamics analysis for 6g revealed a stable conformation within the protein domain during the simulation period. The present work thus opens up the possibility of further exploring the utility of 6g and 6e in delineating their DNA gyrase binding biologically and deducing their mechanistic interventions. The work may further be expanded to recruit more pathogenic-resistant strains, and the inhibitory potential of the compounds may further be analysed.