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Bioorg Med Chem Lett. 2015 Apr 1;25(7):1515-9. doi: 10.1016/j.bmcl.2015.02.020. Epub 2015 Feb 21.

Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure-activity studies.

Author information

1
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
2
Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
3
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States. Electronic address: pcarlier@vt.edu.

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.

KEYWORDS:

Apicoplast; MEP pathway; Malaria; Non-mevalonate; Plasmodium

PMID:
25754494
PMCID:
PMC4374032
DOI:
10.1016/j.bmcl.2015.02.020
[Indexed for MEDLINE]
Free PMC Article

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