Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

Abstract

Target repurposing is a proven method for finding new lead compounds that target <i>Trypanosoma brucei</i>, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog <b>2</b> with excellent potency against <i>T. brucei</i> (EC₅₀ = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound <b>11e</b> to have an EC₅₀ of 84 nM against <i>T. brucei</i> cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas' disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for <i>T. cruzi</i> (<b>4j</b>) and <i>Plasmodium falciparum</i> (<b>11j</b>) were discovered, along with an analog with considerable potency against <i>Leishmania major</i> amastigotes (<b>4e</b>). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites.