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 b-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All beta-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC50: 11.69 microM (K1, chloroquine and multi-drug resistant strain), and 11.78 microM (D10, chloroquine sensitive strain)]—12e was the most active [IC50: 0.63 microM (K1), and 0.61 microM (D10)]. The phenyl and naphthyl b-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the b-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.