期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 13, 期 2, 页码 312-318出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00717
关键词
Trypanosome alternative oxidase inhibitor; Trypanosoma brucei; benzamidine; imidazoline; glycolysis
资金
- Ministerio de Ciencia, Innovacion/Agencia Estatal de Investigacion (European Regional Development Fund, ERDF, A way to build Europe) [MCIN/AEI/10.13039/501100011033, RTI2018-093940-B-I00]
- Japan Society for the promotion of Science (JSPS) [17F17420]
- Libyan government
- Petroleum Technology Development Fund of Nigeria
- Grants-in-Aid for Scientific Research [17F17420] Funding Source: KAKEN
Research showed that modifying the mitochondrion-targeting cations and scaffold of TAO inhibitors affected their in vitro activity, with the addition of polar substituents in the tail region generally having a detrimental impact on enzyme and cellular activity.
The trypanosome alternative oxidase (TAO), a mitochondrial enzyme involved in the respiration of the blood-stream 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.
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