DHA-indole-triazole hybrids: Click mediated synthesis, antimicrobial, antibiofilm and In Silico studies

In recent era, dehydroacetic acid (DHA), indole and 1,2,3-triazole emerged as important scaffolds in medicinal chemistry as they are frequently found in various physiologically active molecules and are playing an important role in modern era drug discovery. In this perspective, herein, we reported a novel series of click derived DHA-indole-triazole hybrids. After successful structural elucidation through various spectral techniques viz. NMR, FT-IR, HRMS, all compounds were evaluated in vitro for antimicrobial and antibiofilm potential against various microbial species. Results of the in vitro study revealed that triazole hybrid (4a) is most effective towards B. subtilis with inhibition rate of 93.8 % (64 μM) and 96.4 % (128 μM) which is comparable with ciprofloxacin (96.71 %). Further, triazole hybrid (4a) also exhibited highest biofilm inhibition (65.47±0.11 %; 128 μM) and biofilm eradication (63.15±0.12 %; 128 μM) against B. subtilis. The in silico molecular docking and molecular dynamics studies were performed to understand the plausible mechanism responsible for the extraordinary potential of triazole hybrid (4a). Results of docking suggests that strong binding interactions between 4a and active sites of targeted enzyme B. subtilis YABJ (PDB ID: 1QD9) with binding energy of -5.00 kcal/mol are responsible for good bioactivity. While, results of the molecular dynamics suggests that there is a stable complexation between 4a and the 1QD9 enzyme with very less RMSD < 2 Å and RMSF < 1 Å values. Principal component analysis (PCA) results gave substantial insights into the structural changes and dynamic behaviour of the protein in the presence of the hybrid 4a.