2. Academic Validation
  3. Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure-Activity Relationship Studies

Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure-Activity Relationship Studies

  • ACS Med Chem Lett. 2022 Jan 28;13(2):312-318. doi: 10.1021/acsmedchemlett.1c00717.
David Cisneros 1,  Eduardo J Cueto-Díaz 1,  Tania Medina-Gil 1,  Rebecca Chevillard 1,  Teresa Bernal-Fraile 1,  Ramón López-Sastre 1,  Mustafa M Aldfer 2,  Marzuq A Ungogo 2,  Hamza A A Elati 2,  Natsumi Arai 3,  Momoka Otani 3,  Shun Matsushiro 3,  Chiaki Kojima 3,  Godwin U Ebiloma 3 4,  Tomoo Shiba 3,  Harry P de Koning 2,  Christophe Dardonville 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2 Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom.
  • 3 Graduate School of Science and Technology, Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • 4 School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, United Kingdom.
PMID: 35178188 DOI: 10.1021/acsmedchemlett.1c00717
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.

Figures