SAR of 4-alkoxybenzoic acid inhibitors of the trypanosome alternative oxidase.

Alejandro Meco Navas, Godwin Ebiloma, Ana Martín Domínguez, Irene Martínez Benayas, Eduardo J. Cueto-Díaz, Amani Saud Alhejely, Emmanuel Oluwadare Balogun, Machi Saito, Miho Matsui, Natsumi Arai, Tomoo Shiba, Shigeharu Harada, Harry P. De Koning, Christophe Dardonville

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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.
Original languageEnglish
Article number923-928
JournalACS Medicinal Chemistry Letters
Issue number9
Publication statusPublished - 31 Jul 2018


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