Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure–activity studies
| Autor: | Emilio F. Merino, Carla Slebodnick, Priscilla Krai, Zhong-Ke Yao, Morgan Simpson, Paul R. Carlier, Maria B. Cassera |
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| Rok vydání: | 2015 |
| Předmět: |
Plasmodium falciparum
Clinical Biochemistry Pharmaceutical Science Stereoisomerism Biochemistry Article Antimalarials Structure-Activity Relationship Parasitic Sensitivity Tests parasitic diseases Drug Discovery medicine Structure–activity relationship Antimalarial Agent Molecular Biology chemistry.chemical_classification Apicoplast Sugar phosphates Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry Methylamide biology.organism_classification Fosmidomycin Erythritol Pipecolic Acids Molecular Medicine Sugar Phosphates Carbolines medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:1515-1519 |
| ISSN: | 0960-894X |
| Popis: | 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 (1 R ,3 S )-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. |
| Databáze: | OpenAIRE |
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