title: Synthesis, in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides.
abstract: A series of 4-aminoquinolinyl-chalcone amides 11-19 were synthesized through condensation of carboxylic acid-functionalized chalcone with aminoquinolines, using 1,1'-carbonyldiimidazole as coupling agent. These compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (W2) strains of Plasmodium falciparum. Their cytotoxicity towards the WI-38 cell line of normal human fetal lung fibroblast was determined. All compounds were found active, with IC50 values ranging between 0.04-0.5μM and 0.07-1.8μM against 3D7 and W2, respectively. They demonstrated moderate to high selective activity towards the parasitic cells in the presence of mammalian cells. However, amide 15, featuring the 1,6-diaminohexane linker, despite possessing predicted unfavourable aqueous solubility and absorption properties, was the most active of all the amides tested. It was found to be as potent as CQ against 3D7, while it displayed a two-fold higher activity than CQ against the W2 strain, with good selective antimalarial activity (SI=435) towards the parasitic cells. During this study, amide 15 was thus identified as the best drug-candidate to for further investigation as a potential drug in search for new, safe and effective antimalarial drugs.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Smit
authors.affiliation: Center of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. Electronic address: david.nda@nwu.ac.za.
authors.forename: David D
authors.initials: DD
authors.lastname: N'da
mesh_terms: D000577:Amides / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured; D002599:Chalcone / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D002738:Chloroquine / Q000494:pharmacology; D003959:Diamines; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000577:Amides; D000962:Antimalarials; D003959:Diamines; D002599:Chalcone; D002738:Chloroquine; C007297:1,6-diaminohexane
keywords: 4-Aminoquinoline; Chalcone; Chloroquine (CQ); Malaria; Plasmodium falciparum