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

Meco-Navas, A. et al. (2018) SAR of 4-alkoxybenzoic acid inhibitors of the trypanosome alternative oxidase. ACS Medicinal Chemistry Letters, 9(9), pp. 923-928. (doi: 10.1021/acsmedchemlett.8b00282) (PMID:30258542)

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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 . Remarkably, two analogues containing the 2-hydroxy-6-methyl scaffold ( and ) displayed single digit nanomolar TAO inhibition, which constitute the most potent 4-alkoxybenzoic acid derivatives described to date. was 50-times more potent against TAO and 10-times more active against compared to its benzaldehyde analogue . The farnesyl derivative was as potent a TAO inhibitor as ascofuranone with IC = 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.

Item Type:Articles
Additional Information:Funding from the Spanish Ministerio de Economia y Competitividad (grant SAF2015-66690-R) is gratefully acknowledged. This research also received funding support from the Japan Society for the promotion of Science (JSPS grant- 17F17420).
Glasgow Author(s) Enlighten ID:Ebiloma, Mr Godwin and De Koning, Professor Harry and Alhejely, Amani Saud
Authors: Meco-Navas, A., Ebiloma, G. U., Martín-Domínguez, A., Martínez-Benayas, I., Cueto-Díaz, E. J., Alhejely, A. S., Balogun, E. O., Saito, M., Matsui, M., Arai, N., Shiba, T., Harada, S., de Koning, H. P., and Dardonville, C.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:ACS Medicinal Chemistry Letters
Publisher:American Chemical Society
Published Online:31 July 2018
Copyright Holders:Copyright © 2018 American Chemical Society
First Published:First published in ACS Medicinal Chemistry Letters 9(9): 923-928
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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