Synthesis, biological evaluation, and structure-activity relationships of N -benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), trypanosomes, and leishmania

Jozef Stec, Qingqing Huang, Marco Pieroni, Marcel Kaiser, Alina Fomovska, Ernest Mui, William H. Witola, Samuel Bettis, Rima McLeod, Reto Brun, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3088-3100
Number of pages13
JournalJournal of medicinal chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Stec, J., Huang, Q., Pieroni, M., Kaiser, M., Fomovska, A., Mui, E., Witola, W. H., Bettis, S., McLeod, R., Brun, R., & Kozikowski, A. P. (2012). Synthesis, biological evaluation, and structure-activity relationships of N -benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), trypanosomes, and leishmania. Journal of medicinal chemistry, 55(7), 3088-3100. https://doi.org/10.1021/jm2015183