To improve the metabolic stability of a 4,4'-oxybisbenzoyl-based novel and potent (nanomolar-range IC50 ) antiplasmodial agent previously described by us, in silico-guided structure-activity relationship (SAR) campaigns have been conducted to substitute its peptide decorations with more metabolically stable residues. The effects of the various structural modifications were then correlated with the antiplasmodial activity in vitro in phenotypic assays. Among the several derivatives synthetized and compared with the 3D-pharmacophoric map of the original lead, a novel compound, characterized by a western tert-butyl glycine residue and an eastern 1S,2S-aminoacyclohexanol, showed low-nanomolar-range antiplasmodial activity, no signs of cross-resistance and, most importantly, 47-fold improved Phase I metabolic stability when incubated with human liver microsomes. These results highlight the efficacy of in silico-guided SAR campaigns which will allow us to further optimize the structure of the new lead aiming at testing its efficacy in vivo using different routes of administration.
Keywords: Antimalarials; In silico pharmacophore mapping; In vitro metabolic stability; Malaria; Plasmodium falciparum.
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