Synthesis, Biological Evaluation, and Structure–Activity Relationships of <i>N</i>-Benzoyl-2-hydroxybenzamides as Agents Active against P. falciparum (K1 strain), Trypanosomes, and Leishmania
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
DOI:10.1021/jm2015183
日期:2012.4.12
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 la 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.