Synthesis, in vitro and in silico investigations of coumarin-benzamide hybrid molecules as urease inhibitors

Enzymes play significant role in a variety of biochemical reactions. Urease is an enzyme that catalyzes the hydrolysis of urea into ammonia and carbamate. Its importance is especially evident in the context of Helicobacter pylori infections which can lead to gastric ulcers and gastrointestinal issues. The main objectives of this research was to synthesize a novel series of coumarin-benzamide hybrid molecules and evaluate their urease inhibitory potential. This study explores the synthesis and urease inhibitory capabilities of novel coumarin hybrids, 4-(((4-methyl-2-oxo-2 H -chromen-7-yl)oxy)methyl)- N -arylbenzamides. The combination of structure–activity relationship (SAR) analysis, enzyme kinetics, and molecular docking studies indicated that these compounds could effectively inhibit urease. The in vitro screening of all the synthesized derivatives ( 5a-n ) resulted in considerable inhibitory effects against urease, with IC 50 values ranging from 0.27 ± 0.01 to 20.1 ± 0.51 µM, surpassing the activity of the standard, thiourea (22.3 ± 0.031 µM). Notably, compound ( 5k ) was identified as the most effective inhibitor, with an IC 50 value of 0.27 ± 0.01 µM. In silico studies indicated the existence of various interactions, including hydrogen bonds, π-alkyl, π-cation and π-sigma interactions with specific amino acid residues. Furthermore, molecular dynamics simulations demonstrated that urease remains stable and flexible in the presence of these inhibitors. These findings suggest that coumarin-based inhibitors could help to manage urease-related infections, and encouraging further exploration of their therapeutic applications.