Discovery of urease inhibitory effect of sulfamate derivatives: Biological and computational studies

Abstract

The discovery of life-changing medicines continues to be the driving force for the rapid exploration and expansion of chemical space, enabling access to innovative small molecules of medicinal importance. These small molecules remain the backbone for modern drug discovery. In this context, the treatment of ureolytic bacterial infections inspires the identification of potent and effective inhibitors of urease, a promising and highly needed target for H. pylori eradication. The present study explores the evaluation of sulfamate derivatives for the inhibition of urease enzyme. The tested compounds showed remarkable inhibitory effect and high level of potency. Compound 1q emerged as the lead inhibitor with an IC50 value of 0.062 ± 0.001 µM, ∼360-fold more potent than thiourea (IC50 = 22.31 ± 0.031 µM). The assessment of various contributing factors towards the inhibition profile allowed for the establishment of diverse structure–activity relationships. Kinetics studies revealed the competitive mode of inhibition of compound 1q while molecular modeling analysis identified various crucial binding interactions with ARG609, ARG439, HIS519, HIS492, HIS593, ALA440, and ALA636 in the active pocket of the enzyme. Finally, the calculated pharmacokinetic properties suggest a promising profile of our potent sulfamate-based urease inhibitors.