European Journal of Medicinal Chemistry p. 489 - 514 (2018)
Update date:2022-08-15
Topics:
Quiliano, Miguel
Pabón, Adriana
Moles, Ernest
Bonilla-Ramirez, Leonardo
Fabing, Isabelle
Fong, Kim Y.
Nieto-Aco, Diego A.
Wright, David W.
Pizarro, Juan C.
Vettorazzi, Ariane
López de Cerain, Adela
Deharo, Eric
Fernández-Busquets, Xavier
Garavito, Giovanny
Aldana, Ignacio
Galiano, Silvia
Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70–73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70–73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds.
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