The need for innovative antiparasitic small molecule treatments for Plasmodium falciparum and Trypanosoma brucei which employ novel mechanisms of action on unique targets has risen as drug resistance to current therapies for malaria and human African trypanosomiasis has spread. From the Tres Cantos Anti-Malarial Set (TCAMS), we identified a purported aspartic protease inhibitor, TCMDC-124587, a spiropiperidine hydantoin. Our optimization efforts showed that derivatives of this compound have antiparasitic activity against P. falciparum and T. brucei, presumably via inhibition of aspartic proteases essential to parasite survival. We have found submicromolar inhibitors with a divergence in their respective structure-activity relationships (SAR) for P. falciparum and T. brucei at the piperidine nitrogen substituent (Figure 1). The synthesis, SAR, and optimization for improved drug-like properties of these novel antiparasitic compounds are discussed.

Evaluation of novel antiparasitic spiropiperidine hydantoins

247th National Meeting (2014)

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