3 years ago

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold
María Luisa León, Gerard Drewes, Michael Witty, Esther Fernández, José M. Coterón, María J. Almela, Jaume Vidal, María José Lafuente-Monasterio, Santiago Ferrer-Bazaga, Francisco J. Gamo, Juan C. de la Rosa, José Ignacio Martín Hernando, Jaime de Mercado, David M. Wilson, Sonja Ghidelli-Disse, Paul Bamborough, Anne Rodríguez, Sara Prats, Benigno Crespo, Félix Calderón, Sophie Huss, Íñigo Angulo-Barturen, Pablo Castañeda, Jeremy Burrows, Lourdes Rueda, María Teresa Fraile, Rubén Gómez, Simon J. F. Macdonald, Beatriz Díaz, María J. Chaparro, Margarita Puente, John Haselden, Nicholas Cammack, María S. Martínez-Martínez, Cristina de Cozar, Elena Sandoval, Paul Willis, Carolyn Selenski, María Belén Jiménez Díaz
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.6b01441

DOI: 10.1021/acs.jmedchem.6b01441

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