Detalle Publicación

2-Phenoxy-3-Trichloromethylquinoxalines are antiplasmodial derivatives with activity against the apicoplast of Plasmodium falciparum

Autores: Amrane, D.; Arnold, C. S.; Hutter, S.; Sanz Serrano, Julen; Collía, M.; Azqueta Oscoz, Amaya; Paloque, L. ; Cohen, A.; Amanzougaghene, N. ; Tajeri, S.; Franetich, J. F. ; Mazier, D.; Benoit-Vical, F.; Verhaeghe, P.; Azas, N. ; Vanelle, P. (Autor de correspondencia); Botte, C. (Autor de correspondencia); Primas, N. (Autor de correspondencia)
Título de la revista: PHARMACEUTICALS
ISSN: 1424-8247
Volumen: 14
Número: 8
Páginas: 724
Fecha de publicación: 2021
The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure-activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 mu M and a HepG2 CC50 value of 32 mu M (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.