ABSTRACT
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 IC50 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. Further, compounds 4b and 5l displayed very good activity with IC50 value of 0.082 ± 0.004 µM and 0.14 ± 0.013 µM respectively compared to standard Acetohydroxamic acid (IC50 - 27.4 ± 1.2 µM). Kinetic studies revealed that a mixed inhibition with both competitive and non-competitive aspects is involved in the urease inhibition mechanism. The in vitro urease inhibition results were supported by molecular docking studies. Collectively, this study indicates that 4g could be considered as promising lead molecule that can be further developed as a potent drug molecule for the treatment of Helicobacter pylori caused gastritis for further studies.
