Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Malaria remains a global health problem, and though international efforts for treatment and eradicationhave made some headway, the emergence of drug-resistant parasites threatens this progress. Antima-larial therapeutics acting via novel mechanisms are urgently required.Plasmodium falciparumM1 andM17 are neutral aminopeptidases which are essential for parasite growth and development. Previouswork in our group has identified inhibitors capable of dual inhibition ofPfA-M1 andPfA-M17, andrevealed further regions within the protease S1 pockets that could be exploited in the development ofligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis ofnovel hydroxamic acid analogues that are capable of potent inhibition of bothPfA-M1 andPfA-M17.Furthermore, the developed compounds potently inhibitPfgrowth in culture, including the multi-drugresistant strain Dd2. The ongoing development of dualPfA-M1/PfA-M17 inhibitors continues to be anattractive strategy for the design of novel antimalarial therapeutics.