Synthesis of 1,2,3-triazole functionalized derivatives of metronidazole as potent inhibitors of urease: Synthesis via click chemistry, in vitro urease inhibition, kinetics and molecular docking studies

Current study is based on multistep synthesis of sixteen new 1,2,3-triazole functionalized derivatives of metronidazole drug 3-18 - 18 by using a Cu(I)-catalysed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) reaction via a click chemistry approach. All the compounds were purified by using conventional silica gel column chromatography with isocratic eluent. Their structures were confirmed by using various spectroscopic techniques including UV, IR, LR and HR MS, 1 H-, 13C NMR , and 2D-NMR spectroscopy. The library of 1,2,3-triazole derivatives of metronidazole 3-18 - 18 was evaluated for urease inhibitory activity, and cytotoxicity against normal cells. Compound 8 (IC50= 50 = 6.8 f 0.8 mu M) was found to be the most potent urease inhibitor, while acetohydroxamic acid (IC50 50 = 20.3 f 0.4 mu M) was used as experimental standard. Compounds 5 (IC50 50 = 7.9 f 0.9 mu M), 6 (IC50 50 = 9.5 f 0.2 mu M), 7 (IC50 50 = 8.5 f 1.0 mu M), 10 (IC50 50 = 9.3 f 1.1 mu M), and 18 (IC50 50 = 7.2 f 0.6 mu M) were also found to be potent inhibitors of urease. Parent drug metronidazole also showed a potent urease enzyme inhibitory activity with IC50= 50 = 10.54 f 0.8 mu M. All compounds were found to be non-cytotoxic against the human fibroblast (B.J.) cell line. Molecular docking and kinetic studies were performed for compounds 5-8, 10 , and 18 which showed that these compounds are competitive inhibitors of urease enzyme inhibition. Urease inhibition is a therapeutic approach to help in the treatment of peptic ulcers, caused by ureolytic bacteria. The initial findings presented herein therefore, deserve further studies.