Imidazoline- and benzamidine-based trypanosome alternative oxidase inhibitors: synthesis and structure–activity relationship studies

Cisneros, D. et al. (2022) Imidazoline- and benzamidine-based trypanosome alternative oxidase inhibitors: synthesis and structure–activity relationship studies. ACS Medicinal Chemistry Letters, 13(2), pp. 312-318. (doi: 10.1021/acsmedchemlett.1c00717) (PMID:35178188) (PMCID:PMC8842630)

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The trypanosome alternative oxidase (TAO), a mitochondrial enzyme involved in the respiration of the bloodstream form trypomastigotes of Trypanosoma brucei, is a validated drug target against African trypanosomes. Earlier series of TAO inhibitors having a 2,4-dihydroxy-6-methylbenzoic acid scaffold (“head”) and a triphenylphosphonium or quinolin-1-ium cation as a mitochondrion-targeting group (“tail”) were shown to be nanomolar inhibitors in enzymatic and cellular assays. We investigated here the effect of different mitochondrion-targeting cations and other scaffold modifications on the in vitro activity of this class of inhibitors. Low micromolar range activities were obtained, and the structure–activity relationship studies showed that modulation of the tail region with polar substituents is generally detrimental to the enzymatic and cellular activity of TAO inhibitors.

Item Type:Articles
Additional Information:Funding: This work was funded by Ministerio de Ciencia, Innovacion/́ Agencia Estatal de Investigació n (MCIN/AEI/10.13039/ 501100011033), through the project RTI2018-093940-B-I00 (co-funded by European Regional Development Fund, ERDF, “A way to build Europe”). This research was also supported by a fellowship grant from the Japan Society for the promotion of Science (JSPS Grant No. 17F17420) to G.U.E. M.M.A. and H.A.A.E. were funded by studentships from the Libyan government. M.A.U. was funded by the Petroleum Technology Development Fund of Nigeria.
Glasgow Author(s) Enlighten ID:Ebiloma, Mr Godwin and De Koning, Professor Harry and Elati, Hamza Ali Abd and Aldfer, Mustafa Mohamed and Ungogo, Mr Marzuq
Authors: Cisneros, D., Cueto-Díaz, E. J., Medina-Gil, T., Chevillard, R., Bernal-Fraile, T., López-Sastre, R., Aldfer, M. M., Ungogo, M. A., Elati, H. A.A., Arai, N., Otani, M., Matsuhiro, S., Kojima, C., Ebiloma, G. U., Shiba, T., 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
ISSN (Online):1948-5875
Published Online:28 January 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in ACS Medicinal Chemistry Letters 13(2): 312-318
Publisher Policy:Reproduced under a Creative Commons licence

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