Synthesis, biological evaluation and mechanistic studies of totarol amino alcohol derivatives as potential antimalarial agents

Abstract

Herein we report on the semisynthesis and biological evaluation of β-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All β-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC50: 11.69μM (K1, chloroquine and multi-drug resistant strain), and 11.78μM (D10, chloroquine sensitive strain)]—12e was the most active [IC50: 0.63μM (K1), and 0.61μM (D10)]. The phenyl and naphthyl β-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the β-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation.