Synergistic Inhibition of Urease by Novel Chromene-Dihidropirimidinone Hybrids: A Combined Synthetic, Biological, and Molecular Dynamics Study

Abstract

This study describes the design, synthesis, and biological evaluation of novel eight chromene-dihydropyrimidinone (Chro-DHPM) hybrids as urease inhibitors. The synthetic approach involved the covalent linkage of chromene and DHPM pharmacophores through a non-enolizable 1,2,3-triazole linker, efficiently constructed via the copper-catalyzed azidealkyne cycloaddition (CuAAC) protocol. Evaluation of antiureolytic activity against urease from Canavalia ensiformis type III revealed that hybrids 4b and 4h were the most potent inhibitors, exhibiting 42.1 and 51.5% inhibition at 100 µM, respectively. These results were compared to thiourea (TIO), used as a positive control, which showed 63.5% inhibition under the same conditions. Furthermore, the hybrids demonstrated significantly enhanced activity compared to their individual precursors, chromene 1a and Biginelli adducts 3b and 3d, thereby highlighting a synergistic effect from molecular hybridization. Molecular dynamics simulations of the most active hybrid, 4h, elucidated a dual binding mechanism wherein the compound stabilizes within the urease active site through coordination of the tetrahydropyrimidine carbonyl oxygen to the binuclear nickel center, combined with steric occlusion of the catalytic entrance by the tetrahydro4H-chromene moiety. Overall, this work demonstrates that molecular hybridization of chromene and DHPM scaffolds represents a promising strategy for developing novel antiureolytic agents.

Keywords:
chromenes; dihydropyrimidinones; hybrid compounds; urease inhibitors; triazole linker