Analogues of the Herbicide, N-Hydroxy-N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads,Journal of Medicinal Chemistry

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Analogues of the Herbicide, N-Hydroxy-N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-29 , DOI: 10.1021/acs.jmedchem.0c01919
Ajit Kandale ₁ , Khushboo Patel ₁ , Waleed M. Hussein ₁ , Shun Jie Wun ₁ , Shan Zheng ₁ , Lendl Tan ₁ , Nicholas P. West ₁ , Gerhard Schenk _{1,

2,

3} , Luke W. Guddat ₁ , Ross P. McGeary ₁

Affiliation

New drugs to treat tuberculosis (TB) are urgently needed to combat the increase in resistance observed among the current first-line and second-line treatments. Here, we propose ketol-acid reductoisomerase (KARI) as a target for anti-TB drug discovery. Twenty-two analogues of IpOHA, an inhibitor of plant KARI, were evaluated as antimycobacterial agents. The strongest inhibitor of Mycobacterium tuberculosis (Mt) KARI has a K_i value of 19.7 nM, fivefold more potent than IpOHA (K_i = 97.7 nM). This and four other potent analogues are slow- and tight-binding inhibitors of MtKARI. Three compounds were cocrystallized with Staphylococcus aureus KARI and yielded crystals that diffracted to 1.6–2.0 Å resolution. Prodrugs of these compounds possess antimycobacterial activity against H37Rv, a virulent strain of human TB, with the most active compound having an MIC₉₀ of 2.32 ± 0.04 μM. This compound demonstrates a very favorable selectivity window and represents a highly promising lead as an anti-TB agent.

中文翻译：

除草剂，N-羟基-N-异丙基草酸酯的类似物，抑制结核分枝杆菌的酮醇酸还原异构酶及其前体药物有望成为抗结核药物的先导

迫切需要新的治疗结核病的药物，以抵抗当前一线和二线治疗中观察到的耐药性增加。在这里，我们建议酮醇酸还原异构酶（KARI）作为抗结核药物发现的目标。评估了植物KARI抑制剂IpOHA的22种类似物作为抗分枝杆菌药物。最强的抑制剂结核分枝杆菌（山）KARI具有ķ_我19.7纳米的值，比五倍IpOHA更有效（ķ_我= 97.7纳米）。这种和其他四个有效的类似物是Mt KARI的缓慢结合和紧密结合抑制剂。三种化合物与金黄色葡萄球菌共结晶KARI并产生衍射至1.6–2.0Å分辨率的晶体。这些化合物的前药对人结核病的强毒株H37Rv具有抗分枝杆菌活性，活性最高的化合物的MIC ₉₀为2.32±0.04μM。该化合物显示出非常有利的选择性窗口，并作为抗结核病药物代表了非常有前途的铅。

更新日期：2021-02-11

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