African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase
| Autor: | Michael Paradowski, Srinivasa P. S. Rao, Paul John Beswick, Gareth Williams, Jamie Laverick, Trevor Askwith, John R. Atack, Oran G. O'Doherty, Ryan West, Lewis E. Pennicott, Simon E. Ward |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Antiprotozoal agents Ubiquinol Alternative oxidase Trypanosoma Ubiquinone 030231 tropical medicine Trypanosoma brucei brucei Medicinal chemistry Pharmacology Biology Article Mitochondrial Proteins 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Drug Discovery medicine Humans African trypanosomiasis Enzyme Inhibitors Plant Proteins Natural product Chemotype Dose-Response Relationship Drug Molecular Structure Drug discovery Organic Chemistry General Medicine medicine.disease Trypanocidal Agents 3. Good health 030104 developmental biology Trypanosomiasis African Ascofuranone chemistry Oxidoreductase Parasitic disease Oxidoreductases Synthesis design QD0241 |
| Zdroj: | European Journal of Medicinal Chemistry |
| ISSN: | 0223-5234 |
| Popis: | African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead. Graphical abstract Image 1 Highlights • Synthesis of ascofuranone like inhibitors of trypanosome alternative oxidase. • Structure activity relationships of trypanosome alternative oxidase inhibitors. • Correlation of trypanosome alternative oxidase inhibition and T. b. brucei growth. |
| Databáze: | OpenAIRE |
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