title: Pentacycloundecylamines and conjugates thereof as chemosensitizers and reversed chloroquine agents.
abstract: The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU-AM derivatives 1-3 showed anti-plasmodial IC50 values in the ranges of 3.74-17.6 nM and 27.6-253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties.
authors.affiliation: School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa. Electronic address: jjoubert@uwc.ac.za.
authors.forename: Jacques
authors.initials: J
authors.lastname: Joubert
authors.affiliation: School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa.
authors.forename: Elton E
authors.initials: EE
authors.lastname: Fortuin
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa.
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D015394:Molecular Structure
chemical_list: D000588:Amines; D000962:Antimalarials; D002738:Chloroquine
keywords: Chloroquine; Malaria; Pentacycloundecylamines; Resistance reversal; Reversed CQ agents