Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.

ABSTRACT: Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct f

SUBMITTER: Bennett JM 

PROVIDER: S-EPMC11457795 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature