Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice
| Autor: | Margaret A. Phillips, David M. Shackleford, Xiaoyi Deng, Karen L. White, Ramesh Gujjar, Frederick S. Buckner, Ian Bathurst, Susan A. Charman, Sharon A. Creason, Jeremy N. Burrows, Pradipsinh K. Rathod, William N. Charman, Farah El Mazouni, David Matthews, David M. Floyd, John H. White |
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| Rok vydání: | 2011 |
| Předmět: |
Oxidoreductases Acting on CH-CH Group Donors
Plasmodium berghei Plasmodium falciparum Dihydroorotate Dehydrogenase Drug resistance Pharmacology Article chemistry.chemical_compound Antimalarials Mice Structure-Activity Relationship parasitic diseases Drug Discovery Structure–activity relationship Animals Humans Enzyme Inhibitors biology Molecular Structure Drug discovery Aryl Triazoles biology.organism_classification Malaria Disease Models Animal Pyrimidines chemistry Biochemistry Drug development Solubility Drug Design Dihydroorotate dehydrogenase Microsomes Liver Molecular Medicine Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 54(11) |
| ISSN: | 1520-4804 |
| Popis: | Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series. |
| Databáze: | OpenAIRE |
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