title: Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency.
abstract: The biosynthesis of coenzyme A (CoA) from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide derivatives of pantothenate, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactive in vivo In this study, we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with 50% inhibitory concentrations (IC50s) of ∼50 nM, and three others have submicromolar IC50s. We show that the compounds target CoA biosynthesis and/or utilization. We investigated one of the compounds for its ability to interact with the Plasmodium falciparum pantothenate kinase, the first enzyme involved in the conversion of pantothenate to CoA, and show that the compound inhibits the phosphorylation of [14C]pantothenate by the P. falciparum pantothenate kinase, but the inhibition does not correlate with antiplasmodial activity. Furthermore, the compounds are not toxic to human cells and, importantly, are not degraded by pantetheinase.
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Howieson
authors.affiliation: Department of Chemistry, McGill University, Montreal, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tran
authors.affiliation: Department of Chemistry, McGill University, Montreal, Canada.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Hoegl
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia.
authors.forename: Han Ling
authors.initials: HL
authors.lastname: Fam
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fu
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Sivonen
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia.
authors.forename: Xiao Xuan
authors.initials: XX
authors.lastname: Li
authors.affiliation: Department of Chemistry, McGill University, Montreal, Canada karine.auclair@mcgill.ca kevin.saliba@anu.edu.au.
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia karine.auclair@mcgill.ca kevin.saliba@anu.edu.au.|Medical School, The Australian National University, Canberra, ACT, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Saliba
mesh_terms: D000577:Amides / Q000737:chemistry; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003065:Coenzyme A / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D010205:Pantothenic Acid / Q000737:chemistry; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000577:Amides; D000962:Antimalarials; D014230:Triazoles; D010205:Pantothenic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A