Discovery of Novel Dihydropyrimidine and hydroxamic acid hybrids as potent Helicobacter pylori Urease inhibitors.

Two novel series of Dihydropyrimidine-hydroxamic acid hybrids (4a-4l and 5a-5l) were designed, synthesized and evaluated for in vitro Helicobacter pylori urease inhibition. In vitro enzyme inhibition screening led to the discovery of three potent urease inhibitors 2-[[4-(4-hydroxy phenyl)-6-oxo-1,6-dihydropyrimidine-2-yl]-amino]-N-hydroxy acetamide (4g), 2-[[4-(4-chloro phenyl)-6-oxo-1,6-dihydropyrimidine-2-yl]-amino]-N-hydroxy acetamide (4b) and 3-[[4-(3-methoxy phenyl)-6-oxo-1,6-dihydropyrimidine-2-yl]-amino]-N-hydroxy propanamide (5l). Compound 4g showed excellent urease inhibition with IC value of 14 ± 1 nM, indicated by its strong interactions with both metallic Ni ions, Gly279, His221, Ala365, Asp362, Asn168, Arg338 and His322 residues of the active site of urease.