SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase.
Basic Information
ID: ALA4196235
Journal: ACS Med Chem Lett
Title: SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase.
Authors: Meco-Navas A, Ebiloma GU, Martín-Domínguez A, Martínez-Benayas I, Cueto-Díaz EJ, Alhejely AS, Balogun EO, Saito M, Matsui M, Arai N, Shiba T, Harada S, de Koning HP, Dardonville C.
Abstract: 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.
CiteXplore: 30258542
DOI: 10.1021/acsmedchemlett.8b00282
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