biostudies-literatureBennett JMCancer Research UKFrancis Crick InstituteNIAID NIH HHSThe Francis Crick InstituteMedical Research CouncilU.S. Department of DefenseNational Institutes of HealthBill and Melinda Gates FoundationWellcome TrustNIGMS NIH HHS1714-1728.e10https://www.ebi.ac.uk/biostudies/studies/S-EPMC11457795biostudies-literatureUnknown31(9)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 fCell chemical biologyMixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.PMC11457795INV-033538R33 AH27581R01 AI141366R01 AI109023220318/A/20/ZW81XWH2210520CC2129T32 GM113854R01 GM145886W81XWII2210520R33 AI127581Yeo TKabeche SMuir RLi VLAbegg DFaucher FFidock DAThathy VBennett JMLovell SAdibekian AYeh EBogyo MBlackman MJHackett FNarwal SKfalseMixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.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 f2024-01-01T00:00:00Z2024 Sep2026-06-02T09:37:40.324Z2026-05-26T03:06:26.41ZS-EPMC114577953913778310.1016/j.chembiol.2024.07.006