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.
Highlights
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
In the absence of a functional oxidative phosphorylation pathway, they use the trypanosome alternative oxidase (TAO) to reoxidize the NADPH that is formed during glycolysis.[3]
The localization of TAO at the interface of the inner mitochondrial membrane[6,7] has inspired the development of potent 4-hydroxybenzoate- and 4-alkoxybenzaldehyde-based inhibitors that hold a lipophilic cation as the mitochondriontargeting moiety.[8−10] In particular, 2,4-dihydroxy-6-methylbenzoate derivatives were nanomolar range TAO inhibitors showing in vitro and in vivo trypanocidal activity in a mouse model of T. b. rhodesiense infection (Chart 1A).[9]
Summary
Chart 1. (A) Example of Previously Reported Benzoate TAO Inhibitors with a Triphenylphosphonium Mitochondrion-Targeting Cation[9] and (B) Structural Modifications Studied in This Work pubs.acs.org/acsmedchemlett. Imidazolin-3-ium (3c) or 4-NO2 (11c) gave less potent inhibitors (IC50 = 22.5 and 30 μM, respectively) These SAR results regarding TAO activity were consistent with previous work showing that the introduction of polar substituents in the tail region of TAO inhibitors is not well-tolerated, leading to a strong decrease in inhibitory potency.[23] This effect seems to be counterbalanced when lipophilic cations such as TPP+ or quinolin-1-ium are used, but in that case, the linker length in the tail region must be long enough (≥C-14) to allow the bulky TPP cation to remain outside the enzyme active site, giving rise to low nanomolar TAO inhibitors.[5,9] For the benzamidine-based TAO inhibitors 1a−d, a linkage of 14 methylene units did not improve TAO inhibition versus the C-. Synthesis and NMR spectra of all the target compounds 1a−d, 2c, 3c, 20, and 21 (PDF)
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