Simplifying nature: Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins
| Autor: | Lindsay B. Tulloch, Gordon J. Florence, Marija K. Zacharova, Terry K. Smith, Andrew L. Fraser, Stefanie K. Menzies, Eoin R. Gould, Elizabeth F. B. King |
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| Přispěvatelé: | The Leverhulme Trust, University of St Andrews. School of Chemistry, University of St Andrews. EaSTCHEM, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. School of Biology |
| Rok vydání: | 2016 |
| Předmět: |
Acetogenins
Stereochemistry medicine.drug_class Cell Survival Trypanosoma cruzi Clinical Biochemistry Tetrahydropyran Triazole Pharmaceutical Science R Medicine (General) 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship SDG 3 - Good Health and Well-being Drug Discovery medicine Structure–activity relationship Humans QD Furans Molecular Biology Nitrofuran Neglected tropical diseases Butenolide Trypanocidal agent Leishmania major Natural products Natural product biology 010405 organic chemistry Organic Chemistry DAS Triazoles biology.organism_classification QD Chemistry R1 Trypanocidal Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Drug Design Acetogenin Molecular Medicine HeLa Cells |
| Zdroj: | Bioorganicmedicinal chemistry. 25(22) |
| ISSN: | 1464-3391 |
| Popis: | This work was funded by the Leverhulme Trust. The research data supporting this publication can be accessed at http://dx.doi.org/10.17630/1dd8b881-17c2-48e4-a72f-53af938f4537. The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the worlds very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity- several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor. Postprint |
| Databáze: | OpenAIRE |
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