N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
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N-单芳基乙酰硫脲作为有效的脲酶抑制剂：合成、SAR 和生物学评价
DOI：
10.1080/14756366.2019.1706503
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Zhu, Hai-Liang
中科院分区：
文献类型：
--
作者：
Li, Wei-Yi;Ni, Wei-Wei;Zhu, Hai-Liang
摘要一种体内分布良好的尿素酶抑制剂被认为是治疗幽门螺杆菌等产尿素酶细菌感染的替代药物。在这里，我们报告了一系列N-单取代硫脲，它们作为有效的尿素酶抑制剂，具有非常低的细胞毒性。一种化合物(B19)被详细评估，并显示出作为治疗幽门螺杆菌引起的疾病的药物的进一步开发的有希望的特征。B19对提取的尿素酶和完整细胞中的尿素酶均有较好的抑制作用，其IC50值分别为0.16 ± 0.05和3.86 ± 0.10 µM，分别是临床用药AHA的170倍和44倍。对接模拟表明，单取代的硫脲部分穿透了尿素结合部位。此外，b19是一种快速、可逆的尿素酶抑制剂，对尿素酶表现出NM亲和力，并从催化区解离(koff=1.6 0 × 10−3 S−1)。
Abstract A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (k off=1.60 × 10−3 s−1) from the catalytic domain.