Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC value of 1.2 μM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development.

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新型脲酶抑制剂三唑酮/恶二唑酮的合成及生物学评价

脲酶是传染性胃炎和胃溃疡的主要毒力因子。脲酶抑制剂被认为是治疗此类疾病的首选药物。基于三唑酮/恶二唑酮骨架，一种能够特异性结合脲酶活性口袋并阻止尿素水解的类尿素片段，我们设计并合成了45种三唑酮/恶二唑酮作为脲酶抑制剂。 8个化合物被证明对脲酶具有优异的抑制活性，比临床上使用的脲酶抑制剂乙酰氧肟酸更有效。最活跃的抑制剂 IC 值为 1.2 μM，其效力比阳性对照高 20 倍以上。酶动力学测定表明，这些新型抑制剂以混合竞争机制可逆地抑制脲酶。分子对接为酶测定中的观察结果提供了证据。此外，这些新型抑制剂被证明是类药物化合物，对哺乳动物细胞具有极低的细胞毒性和良好的水溶性。这些结果表明，三唑酮和恶二唑酮是设计和发现新型脲酶抑制剂的有前途的支架，并有望成为进一步药物开发的良好候选者。