Novel Sulfamide-Hydroxamic Acids Containing Piperazine/Piperidine Segment as Potent Urease Inhibitors: Synthesis, Biological Evaluation, Kinetics and Molecular Docking Studies

Abstract

Urease is known as a virulence factor of some pathogen resulting a variety of diseases such as peptic ulcers, gastric cancer, pyelonephritis, and kidney stone. In this paper, a novel series of sulfamide-hydroxamic acids containing piperazine/piperidine segment were designed, synthesized, and evaluated as urease inhibitors. All the synthesized compounds (d1-d16, and d17-d33) having IC50 values ranging of 0.29-20.3 μM were more potent than the clinically used inhibitor acetohydroxamic acid (AHA, IC50 = 23.4±1.6 μM), with the most active inhibitor (d4) being over 80 times than that of AHA. These novel urease inhibitors were proved to reversibly inhibit urease with mixed mechanism, had almost no cytotoxicity to mammalian cells at a concentration of 250 μg/mL, and showed favorable water solubility with drug-likeness. These positive results give a guarantee for further bioassays to develop a new drug candidate.

Keywords: Sulfamidehydroxamic acid, Urease inhibitor, Cytotoxicity, Enzyme kinetics, Molecular docking