title: Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure-activity studies.
abstract: Compounds that target isoprenoid biosynthesis in Plasmodium falciparum could be a welcome addition to malaria chemotherapy, since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. We previously reported that MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. In this Letter, we determine that the active stereoisomer of MMV008138 is 4a, which is (1R,3S)-configured. 2',4'-Disubstitution of the D ring was also found to be crucial for inhibition of the parasite growth. Limited variation of the C3-carboxylic acid substituent was carried out, and methylamide derivative 8a was found to be more potent than 4a; other amides, acylhydrazines, and esters were less potent. Finally, lead compounds 4a, 4e, 4f, 4h, 8a, and 8e did not inhibit growth of Escherichia coli, suggesting that protozoan-selective inhibition of the MEP pathway of P. falciparum can be achieved.
authors.affiliation: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Zhong-Ke
authors.initials: ZK
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Priscilla M
authors.initials: PM
authors.lastname: Krai
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Emilio F
authors.initials: EF
authors.lastname: Merino
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Simpson
authors.affiliation: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Carla
authors.initials: C
authors.lastname: Slebodnick
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Cassera
authors.affiliation: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States. Electronic address: pcarlier@vt.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004896:Erythritol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010875:Pipecolic Acids / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013403:Sugar Phosphates / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C114232:2-C-methylerythritol 4-phosphate; D000962:Antimalarials; D002243:Carbolines; C000591635:MMV008138; D010875:Pipecolic Acids; D013403:Sugar Phosphates; D004896:Erythritol
keywords: Apicoplast; MEP pathway; Malaria; Non-mevalonate; Plasmodium