Generation of Oxamic Acid Libraries: Antimalarials and Inhibitors of Plasmodium falciparum Lactate Dehydrogenase
| العنوان: | Generation of Oxamic Acid Libraries: Antimalarials and Inhibitors of Plasmodium falciparum Lactate Dehydrogenase |
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| المؤلفون: | Anupam Pradhan, Mitchell A. Avery, E. Blake Watkins, Aaron B. Beeler, John M. Rimoldi, Seoung-Ryoung Choi, Babu L. Tekwani |
| المصدر: | Journal of Combinatorial Chemistry. 9:292-300 |
| بيانات النشر: | American Chemical Society (ACS), 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Models, Molecular, Magnetic Resonance Spectroscopy, Plasmodium falciparum, Antimalarials, chemistry.chemical_compound, Chloroquine, Lactate dehydrogenase, medicine, Animals, Antimalarial Agent, Enzyme Inhibitors, chemistry.chemical_classification, Oxamic Acid, L-Lactate Dehydrogenase, biology, Substrate (chemistry), Active site, General Chemistry, biology.organism_classification, Amino acid, Enzyme, Biochemistry, chemistry, biology.protein, medicine.drug |
| الوصف: | Lactate dehydrogenase (LDH) is a key enzyme in the glycolytic pathway of Plasmodium falciparum (pf) and has several unique amino acids, related to other LDHs, at the active site, making it an attractive target for antimalarial agents. Oxamate, a competitive inhibitor, shows high substrate affinity for pfLDH. This class of compounds has been viewed as potential antimalarial agents. Thus, we have developed an effective automated synthetic strategy for the rapid synthesis of oxamic acid and ester libraries to screen for potential lead inhibitors. One hundred sixty-seven oxamic acids were synthesized using a "catch and release" method with overall yields of 20-70%. Most of the compounds synthesized had some inhibitory effects, but compounds 5 and 6 were the most active against both chloroquine- and mefloquine-resistant strains with IC50 values of 15.4 and 9.41 microM and 20.4 and 8.40 microM, respectively. Some oxamic acids showed activities against pfLDH and mammalian LDH (mLDH) at the micromolar range. These oxamic acids selectively inhibited pfLDH 2-5 fold over mLDH. Oxamic acid 21 was the most active against pfLDH at IC50 = 14 and mLDH at IC50 = 25 microM, suggesting that oxamic acid derivatives are potential inhibitors of pfLDH and that further study is required to develop selective inhibitors of pfLDH over mLDH. |
| تدمد: | 1520-4774 1520-4766 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ad8b00bc8d17d1eef235466508bc3719Test https://doi.org/10.1021/cc060110nTest |
| رقم الانضمام: | edsair.doi.dedup.....ad8b00bc8d17d1eef235466508bc3719 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204774 15204766 |
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