Multistage Antimalarial Inhibitors From Diversity-Oriented Synthesis and C-H Activation

Abstract

The malaria parasite has three distinct life cycle stages in humans, yet most antimalarial drugs only target one of those stages: the symptomatic blood stage. Additionally, the emergence of parasite resistance has rendered many antimalarials ineffective in certain geographical contexts, underscoring the need for new, multistage antimalarials with novel mechanisms of action. This dissertation introduces three such compounds. First, a series of spirocycles targeting PI(4)K with activity against three parasite stages is briefly described. Next, a series of azetidine-2-carbonitriles targeting dihydroorotate dehydrogenase (DHODH) is described. This compound family displays activity against liver and blood stages of the Plasmodium life cycle. Analysis of structure-activity relationships identified BRD1331, which demonstrates excellent biochemical selectivity, potency against patient-derived strains of P. falciparum and P. vivax, and robust parasite clearance in two in vivo mouse models. Finally, a series of bicyclic azetidines targeting phenylalanyl tRNA synthetase with activity against three parasite stages is introduced. Following a retrosynthetic analysis, a Pd-catalyzed C(sp3)-H arylation of azetidines at the C3 position is described. This methodology exhibits broad substrate scope and provides C3-arylated azetidines, pyrrolidines, and piperidines. Application of this reaction gave access to valuable, stereochemically defined building blocks, enabling an efficient synthesis of antimalarial compound BRD3914. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.