Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 15, Pages 4163-4171Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.06.044
Keywords
Antiplasmodial; 4-Aminoquinoline; CuAAC click chemistry; Triazole linkers; Resistance reversal
Funding
- Stellenbosch University
- National Research Foundation (NRF South Africa)
- NRF MSc
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The synthesis and in vitro evaluation of novel triazole-linked chloroquinoline derivatives as potential antiplasmodial agents against Plasmodium falciparum is reported. The 15 synthesized target compounds were obtained by means of a copper(I)-mediated click reaction between a variety of 1,2- and 1,3-azidoamines and 7-chloro-N-(prop-2-yn-1-yl) quinolin-4-amine in moderate to good yields (53-85%). The compounds were screened for antiplasmodial activity against NF54 chloroquine-sensitive and Dd2 chloroquine-resistant strains, alongside chloroquine and artesunate as reference compounds. Six of the test compounds revealed a 3-5 fold increase in antiplasmodial activity against chloroquine-resistant strain Dd2 compared to chloroquine. Among the six compounds with good antiplasmodial activity, a reduced cross-resistance relative to artesunate (>3 fold in comparison to chloroquine) was observed, mainly in derivatives that incorporated chloroquine-resistance reversing pharmacophores. A general trend for reduced chloroquine cross-resistance was also detected among 12 out of the 15 compounds tested. (C) 2015 Elsevier Ltd. All rights reserved.
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