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: Jacques Joubert, Elton E Fortuin, Dale Taylor, Peter J Smith, Sarel F Malan
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 23 Pg. 5516-9 (Dec 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 25451997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Amines
• Antimalarials
• Chloroquine

Topics

• Amines (chemistry, metabolism)
• Antimalarials (pharmacology)
• Chloroquine (pharmacology)
• Humans
• Malaria (drug therapy)
• Molecular Structure