The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold
| Autor: | Elena Sandoval, Maria Santos Martinez-Martinez, Beatriz Hernández Díaz, Esther Fernández, Maria Jose Lafuente-Monasterio, Jeremy N. Burrows, Simon J. F. Macdonald, Sara Prats, John N. Haselden, Gerard Drewes, Pablo Castañeda, Francisco J. Gamo, J. Vidal, Jose Ignacio Martin Hernando, Benigno Crespo, Margarita Puente, David Matthew Wilson, Paul Bamborough, María Luisa León, Maria Jesus Almela, Sonja Ghidelli-Disse, Rubén M. Gómez, Jaime de Mercado, Carolyn Selenski, Jose M. Coteron, Anne Rodríguez, Cristina de Cozar, Michael J Witty, Juan C. de la Rosa, Paul Willis, Iñigo Angulo-Barturen, María J. Chaparro, Lourdes Rueda, Félix Calderón, Nicholas Cammack, Santiago Ferrer-Bazaga, Sophie Huss, María T. Fraile, María Belén Jiménez Díaz |
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| Rok vydání: | 2017 |
| Předmět: |
Scaffold
Antiparasitic medicine.drug_class Plasmodium falciparum Pharmacology Parasitemia 01 natural sciences Antimalarials Mice Structure-Activity Relationship 2 2'-Dipyridyl Drug Discovery medicine Animals Humans Artemisinin Mode of action Atovaquone Oxadiazoles Virtual screening Aqueous medium Mutagenicity Tests 010405 organic chemistry Chemistry Chloroquine 0104 chemical sciences 010404 medicinal & biomolecular chemistry Hydrazines Pyrimethamine Drug Design Molecular Medicine Female Pharmacophore Mutagens medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 60:6880-6896 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01441 |
| Popis: | Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile. |
| Databáze: | OpenAIRE |
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