Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane
| Autor: | Brian R Blank, Jiri Gut, Adam R. Renslo, Philip J. Rosenthal |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Plasmodium berghei
Antiparasitic medicine.drug_class Stereochemistry Plasmodium falciparum 010402 general chemistry 01 natural sciences Article Antimalarials Heterocyclic Compounds 1-Ring Mice Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics In vivo Drug Discovery medicine Animals Spiro Compounds Reactivity (chemistry) Ferrous Compounds Arterolane biology 010405 organic chemistry Chemistry Enantioselective synthesis Stereoisomerism biology.organism_classification In vitro Malaria Peroxides 0104 chemical sciences 3. Good health Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00699 |
| Popis: | We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that trans-3″-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4″ comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., 12i) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials. |
| Databáze: | OpenAIRE |
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