The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold
2017; American Chemical Society; Volume: 60; Issue: 16 Linguagem: Inglês
10.1021/acs.jmedchem.6b01441
ISSN1520-4804
AutoresElena Sandoval, María José Lafuente-Monasterio, María Jesús Almela, Pablo Castañeda, María Belén Jiménez Díaz, María Santos Martínez, Jaume Vidal, Íñigo Angulo‐Barturen, Paul Bamborough, Jeremy N. Burrows, N. Cammack, María J. Chaparro, José M. Coterón, Cristina de Cózar, Benigno Crespo, Beatriz Díaz, Gerard Drewes, Esther Fernández, Santiago Ferrer, María Fraile, Francisco‐Javier Gamo, Sonja Ghidelli-Disse, Rubén M. Gómez, John N. Haselden, Sophie Huss, María Luisa León, Jaime de Mercado, Simon J. F. Macdonald, José Ignacio Martı́n Hernando, Sara Prats, Margarita Puente, Anne Rodríguez, Juan Carlos de la Rosa, Lourdes Rueda, Carolyn Selenski, Paul Willis, David M. Wilson, Michael J. Witty, Félix Calderón,
Tópico(s)Computational Drug Discovery Methods
ResumoSince 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.
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