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基于咪唑啉和苯甲脒的锥虫交替氧化酶抑制剂：合成及构效关系研究

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

作者信息

Cisneros David, Cueto-Díaz Eduardo J, Medina-Gil Tania, Chevillard Rebecca, Bernal-Fraile Teresa, López-Sastre Ramón, Aldfer Mustafa M, Ungogo Marzuq A, Elati Hamza A A, Arai Natsumi, Otani Momoka, Matsushiro Shun, Kojima Chiaki, Ebiloma Godwin U, Shiba Tomoo, de Koning Harry P, Dardonville Christophe

机构信息

Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom.

出版信息

ACS Med Chem Lett. 2022 Jan 28;13(2):312-318. doi: 10.1021/acsmedchemlett.1c00717. eCollection 2022 Feb 10.

DOI:10.1021/acsmedchemlett.1c00717
PMID:35178188
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8842630/
Abstract

The trypanosome alternative oxidase (TAO), a mitochondrial enzyme involved in the respiration of the bloodstream form trypomastigotes of , 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.

摘要

锥虫交替氧化酶（TAO）是一种参与布氏锥虫血流型锥鞭毛体呼吸作用的线粒体酶，是针对非洲锥虫的一个经过验证的药物靶点。早期一系列具有2,4 - 二羟基 - 6 - 甲基苯甲酸支架（“头部”）和三苯基鏻或喹啉 - 1 - 鎓阳离子作为线粒体靶向基团（“尾部”）的TAO抑制剂在酶促和细胞试验中显示为纳摩尔级抑制剂。我们在此研究了不同线粒体靶向阳离子和其他支架修饰对这类抑制剂体外活性的影响。获得了低微摩尔范围的活性，结构 - 活性关系研究表明，用极性取代基调节尾部区域通常对TAO抑制剂的酶促和细胞活性不利。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/21784beb72bc/ml1c00717_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/11f828204593/ml1c00717_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/5893ee7e6551/ml1c00717_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/43d701074c1f/ml1c00717_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/1674b2f3c378/ml1c00717_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/21784beb72bc/ml1c00717_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/11f828204593/ml1c00717_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/5893ee7e6551/ml1c00717_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/43d701074c1f/ml1c00717_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/1674b2f3c378/ml1c00717_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e777/8842630/21784beb72bc/ml1c00717_0002.jpg

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