Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery

Abstract 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 (IC 50 s  55 , 56 , 64 , 70 , 71 , and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s  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.