title: In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine.
abstract: 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.
authors.affiliation: Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Lebusetsa
authors.initials: L
authors.lastname: Taleli
authors.affiliation: Division of Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.affiliation: Division of Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pelly
authors.affiliation: Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Margaret A L
authors.initials: MAL
authors.lastname: Blackie
authors.affiliation: Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa. Electronic address: wvo@sun.ac.za.
authors.forename: Willem A L
authors.initials: WAL
authors.lastname: van Otterlo
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D002738:Chloroquine / Q000737:chemistry*; D057930:Click Chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004351:Drug Resistance / Q000187:drug effects; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D014230:Triazoles; D000077332:Artesunate; D002738:Chloroquine
keywords: 4-Aminoquinoline; Antiplasmodial; CuAAC click chemistry; Resistance reversal; Triazole linkers