4-Oxycoumarinyl linked acetohydrazide Schiff bases as potent urease inhibitors

Abstract

Urease enzyme is responsible to catalyze the hydrolysis of urea into carbamate and ammonia. Then carbamate hydrolyzed to ammonia and carbon dioxide. Excess release of ammonia leads to increase pH in stomach that actually encourages the survival of Helicobacter pylori. H. pylori involves in various disorders most commonly peptic ulcer, pyelonephritis, hepatic coma, kidney stone formation, urolithiasis, and encephalopathy. Apart from many pharmacological properties, coumarin and Schiff bases are known to possess urease inhibitory activity. Therefore, these two pharmacologically important scaffolds are combined into single hybrid molecules to assess their potential as urease inhibitors. For this aim, N′-benzylidene-2-((2-oxo-2H-chromen-4-yl)oxy)acetohydrazide Schiff base derivatives 3–27 were synthesized by following a three step reaction strategy. Structures of all synthetic molecules were characterized by EI-MS, 1H-, and 13C NMR spectroscopic techniques. All molecules were assessed for urease inhibitory activity and found to possess a varying degree of inhibitory potential in the range of IC50 = 12.3 ± 0.69 to 88.8 ± 0.04 μM. Amongst the active analogs, compounds 7 (IC50 = 16.2 ± 0.11 μM), 9 (IC50 = 15.2 ± 0.14 μM), 10 (IC50 = 12.3 ± 0.69 μM), 12 (IC50 = 16.3 ± 0.45 μM), and 15 (IC50 = 17.6 ± 0.28 μM) were identified as potent inhibitors compared to standard urea (IC50 = 21.5 ± 0.47 μM). It is conferred from structure-activity relationship (SAR) that variation in inhibitory activity is due to different substitutions pattern on aryl ring. Moreover, molecular docking studies were carried out to understand the interactions of ligand with the active pocket of urease enzyme.