Novel sulfamide-hydroxamic acids containing piperazine/piperidine segment as potent urease inhibitors: Synthesis, biological evaluation, kinetics and molecular docking studies

Urease is known as a virulence factor of some pathogen resulting a variety of diseases such as peptic ulcers, gastric cancer, pyelonephritis, and kidney stones. 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 from 0.29 to 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 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.