Synthesis, Biological Evaluation, and Structure鈥揂ctivity Relationships of N-Benzoyl-2-hydroxybenzamides as Agents Active against P. falciparum (K1 strain), Trypanosomes, and Leishmania

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• 作者：Jozef Stec ; Qingqing Huang ; Marco Pieroni ; Marcel Kaiser ; Alina Fomovska ; Ernest Mui ; William H. Witola ; Samuel Bettis ; Rima McLeod ; Reto Brun ; Alan P. Kozikowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3088-3100
• 全文大小：458K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.