title: 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 [IC(50): 11.69 μM (K1, chloroquine and multi-drug resistant strain), and 11.78 μM (D10, chloroquine sensitive strain)]-12e was the most active [IC(50): 0.63 μM (K1), and 0.61 μM (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.
authors.affiliation: Division of Pharmacology, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Claire
authors.initials: C
authors.lastname: Tacon
authors.forename: Eric M
authors.initials: EM
authors.lastname: Guantai
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D045784:Abietanes; D000605:Amino Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002738:Chloroquine / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000737:chemistry*; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects*; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D045784:Abietanes; D000605:Amino Alcohols; D000962:Antimalarials; D004224:Diterpenes; D010616:Phenanthrenes; D011412:Propanolamines; C078548:totarol; D002738:Chloroquine