SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase
SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase
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DOI：
10.1021/acsmedchemlett.8b00282
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发表时间：
2018-09-01
影响因子：
4.2
通讯作者：
Dardonyille, Christophe
中科院分区：
文献类型：
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作者：
Meco-Navas, Alejandro;Ebiloma, Godwin U.;Dardonyille, Christophe
研究了锥虫交替氧化酶（TAO）抑制剂4-羟基苯甲醛的SAR，TAO是血液形式锥虫呼吸的关键酶。用甲酯取代醛基导致TAO抑制和抗T.布鲁塞。值得注意的是，含有2-羟基-6-甲基支架的两种类似物（9 e和16 e）显示出个位数纳摩尔TAO抑制，其构成迄今为止描述的最有效的4-烷氧基苯甲酸衍生物。9 e对TAO的活性是TAO的50倍，对T的活性是T的10倍。与其苯甲醛类似物1相比，法呢基衍生物16 e是与Ascofuranone一样有效的TAO抑制剂，IC 50 = 3.1 nM。类似于ascofuranone衍生物，2-羟基和6-甲基似乎是必不可少的低纳摩尔TAO抑制酸衍生物，这表明类似的结合与TAO活性位点的相互作用。
The SAR of 4-hydroxybenzaldehyde inhibitors of the trypanosome alternative oxidase (TAO), a critical enzyme for the respiration of bloodstream forms of trypanosomes, was investigated. Replacing the aldehyde group with a methyl ester resulted in a 10-fold increase in TAO inhibition and activity against T. brucei. Remarkably, two analogues containing the 2-hydroxy-6-methyl scaffold (9e and 16e) displayed single digit nanomolar TAO inhibition, which constitute the most potent 4-alkoxybenzoic acid derivatives described to date. 9e was 50-times more potent against TAO and 10-times more active against T. brucei compared to its benzaldehyde analogue 1. The farnesyl derivative 16e was as potent a TAO inhibitor as ascofuranone with IC50 = 3.1 nM. Similar to ascofuranone derivatives, the 2-hydroxy and 6-methyl groups seemed essential for low nanomolar TAO inhibition of acid derivatives, suggesting analogous binding interactions with the TAO active site.