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

Bioorganic & Medicinal Chemistry Letters
Zhong-Ke YaoPaul R Carlier

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.

References

Jun 3, 2006·Science·Steven R GillKaren E Nelson
Aug 19, 2007·Antimicrobial Agents and Chemotherapy·Erica L Dahl, Philip J Rosenthal

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Citations

Sep 30, 2016·Frontiers in Microbiology·Gagandeep S SagguVishal Saxena
Nov 8, 2017·Antimicrobial Agents and Chemotherapy·Taher UddinChristopher Dean Goodman
Aug 31, 2016·Antimicrobial Agents and Chemotherapy·Erik L AllmanManuel Llinás
Aug 7, 2019·Biochemical Society Transactions·Marco Biddau, Lilach Sheiner
Jan 12, 2021·Journal of Biomolecular Structure & Dynamics·Josiane V CruzCleydson B R Santos
Jun 1, 2021·European Journal of Medicinal Chemistry·Aarzoo KambojDeepak B Salunke
Sep 4, 2021·European Journal of Medicinal Chemistry·Jiayun WangXin Chen
Oct 2, 2020·Mini Reviews in Medicinal Chemistry· FaheemMurugesan Sankaranarayanan

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Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.