Design, synthesis, in vitro evaluation, and molecular dynamics simulation studies of novel coumarin-acetohydrazide Schiff base derivatives as urease enzyme inhibitors

Abstract

Urease inhibition, a nickel-containing metalloenzyme, is a promising approach for treating Helicobacter pylori (H. pylori) infections as a critical virulence factor that allows the bacteria to colonize the gastric mucosa and survive the acidic environment of the stomach. In this context, we report the design, synthesis, in vitro evaluation, and molecular dynamics simulation (MD) studies of novel ((4,7-dimethyl-2-oxo-2H-chromen-5-yl)oxy)acetohydrazide derivatives as urease enzyme inhibitors. Notably, all compounds exhibited potent inhibitory activities, with IC₅₀ values ranging from 2.438 µM to 4.427 µM. Further kinetic studies revealed that compound 11g as the most potent compound with IC₅₀ value of 2.438 ± 0.31 μM acts as a non-competitive inhibitor toward urease with an inhibition constant (Ki) of 2.33 μM. In silico studies elucidated the binding interactions of compound 11g, revealing crucial hydrogen bonds with key amino acid residues as well as chelation with Ni ions within the active site of urease. Molecular dynamics (MD) simulations confirmed the stable ligand-urease complex maintains interactions with both the active site residues and the flap moiety of urease, acting as noncompetitive inhibitors. These findings demonstrate the potential of coumarin-acetohydrazide Schiff base derivatives as a new frontier in developing urease inhibitors.