Azole‐based non‐peptidomimetic plasmepsin inhibitors

Kinena, L.; Leitis, G.; Kanepe-Lapsa, I.; Bobrovs, R.; Jaudzems. K.; Ozola, V.; Suna, E.; Jirgensons, A. Arch. Pharm. Chem. Life Sci. 2018, 351, 1800151.

DOI: 10.1002/ardp.201800151


The spread of drug‐resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases – plasmepsins (Plms) – are differentially expressed in multiple stages of the Plasmodium parasite’s lifecycle and are considered as attractive drug targets. We report the development of novel azole‐based non‐peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino‐piperazine inhibitors. The best triazole‐based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance‐free antimalarial drug targeting the non‐digestive Plm IX or X, which are essential for the malaria parasite life cycle.