Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
J Med Chem. 2012 Apr 12;55(7):3088-100. doi: 10.1021/jm2015183. Epub 2012 Mar 20.
In our efforts to identify novel chemical scaffolds for the development of new antiprotozoal drugs, a compound library was screened against Toxoplasma gondii tachyzoites with activity discovered for N-(4-ethylbenzoyl)-2-hydroxybenzamide 1a against T. gondii as described elsewhere. Synthesis of a compound set was guided by T. gondii SAR with 1r found to be superior for T. gondii , also active against Thai and Sierra Leone strains of Plasmodium falciparum , and with superior ADMET properties as described elsewhere. Herein, synthesis methods and details of the chemical analysis of the compounds in this series are described. Further, this series of N-benzoyl-2-hydroxybenzamides was repurposed for testing against four other protozoan parasites: Trypanosoma brucei rhodesiense , Trypanosoma cruzi , Leishmania donovani , and P. falciparum (K1 isolate). Structure-activity analyses led to the identification of compounds in this set with excellent antileishmanial activity (compound 1d). Overall, compound 1r was the best and had activity 21-fold superior to that of the standard antimalarial drug chloroquine against the K1 P. falciparum isolate.
在我们努力寻找新型化学支架以开发新的抗寄生虫药物的过程中，我们对含有化合物的文库进行了筛选，以检测其对刚地弓形虫速殖子的活性。化合物 1a 在其他地方被描述为对刚地弓形虫具有活性，因此被发现具有活性。根据刚地弓形虫的 SAR 进行了化合物集的合成，结果发现 1r 对刚地弓形虫更为有效，也对泰国和塞拉利昂的恶性疟原虫株有效，并且具有更好的 ADMET 特性，如其他地方所述。本文描述了该系列化合物的合成方法和化学分析细节。此外，该系列的 N-苯甲酰-2-羟基苯甲酰胺被重新用于测试四种其他原生动物寄生虫：布氏锥虫罗得西亚亚种、克氏锥虫、杜氏利什曼原虫和恶性疟原虫（K1 株）。结构活性分析确定了该化合物具有良好的抗利什曼原虫活性（化合物 1d）。总的来说，化合物 1r 的效果最好，对 K1 恶性疟原虫株的活性比标准抗疟药物氯喹高出 21 倍。
