Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2015-08, Vol.78 (8), p.1848-1858
• Main Authors: Wilhelm, Anke, Kendrekar, Pravin, Noreljaleel, Anwar E. M, Abay, Efrem T, Bonnet, Susan L, Wiesner, Lubbe, de Kock, Carmen, Swart, Kenneth J, van der Westhuizen, Jan Hendrik
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cell Survival - drug effects; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Chloroquine - pharmacology; CHO Cells; Combinatorial Chemistry Techniques; Cricetinae; Cricetulus; Drug Resistance - drug effects; Inhibitory Concentration 50; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Parasitic Sensitivity Tests; Plasmodium falciparum; Plasmodium falciparum - drug effects; Structure-Activity Relationship
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.5b00114

A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1–55) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC50 values similar to or better than chloroquine (CQ). The most active compound (26) had an IC50 value of 0.01 μM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices.