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)
Text
263739.pdf - Published Version Available under License Creative Commons Attribution. 1MB |
Abstract
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. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Aldfer, Mustafa Mohamed and Ebiloma, Mr Godwin and Elati, Hamza Ali Abd and Ungogo, Mr Marzuq and De Koning, Professor Harry |
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: | 1948-5875 |
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 |
University Staff: Request a correction | Enlighten Editors: Update this record