Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent <i>In Vitro</i> and <i>In Vivo</i> Antimalarial Activity

Abstract

The <i>Plasmodium falciparum</i> aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in <i>in vitro</i> parasite growth inhibition. Inhibitor <b>7k</b> cleared blood-stage <i>P. falciparum</i> in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound <b>7k</b> represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.