Synthesis, photoisomerization and antimalarial activities of cinnamoyl chloroquinoline hybrids

M.Sc. (Chemistry)

Department of Chemistry

The primary aim of this project was to synthesize a series of cinnamoyl chloroquinoline hybrids employing a technique of molecular hybridization. Cinnamoyl chloroquinoline hybrids are compounds with the heteroaromatic core of amino-7-chloroquinoline, linked to differently substituted cinnamic acid groups by flexible primary diamines. In this study, three series (n=2, 3 and 6) of nineteen cinnamoyl chloroquinoline hybrids 18-36 were successfully synthesized by modifying known conventional methods with yields ranging from 24-74%. The structures of synthesized compounds were characterized by a combination of 1H NMR, 13C NMR, HRMS and IR analysis. Hybrids 18-36 were found to isomerize when exposed to light to form mixture of cis and trans isomers. Through chromatographic mass spectrometry (LC-MS), these isomers were studied and LC-Q-TOF-MS/MS analyses of the photo-products revealed the emergence of cis isomer which eluted before its synthesized trans counterpart, suggesting a reduced polarity. The polarity of the compounds was significantly influenced by the nature of the substituents attached to the phenyl ring. Electron-withdrawing groups such as Cl, NO2, and F increased polarity in contrast to electron donating group OCH3 which reduced polarity. The concept of photoisomerization of cinnamoyl chloroquinoline hybridswere validated by the measurement of the transformation of trans to cis isomers using 1H NMR. Compounds 18-36 were tested against wild-type drug-sensitive strain (NF54) and multidrug-resistant isolate (K1) of the human malaria parasite Plasmodium falciparum. Compounds with longer alkyl carbon chain linkers demonstrated greater antiplasmodial activity compared to those with shorter chain linkers. The in vitro studies revealed that compound 32 showed the most potent activity (in vitro 50% inhibitory concentration, 0,012 μM for strain NF54 and 0,009 μM for strain K1 and resistance index of 0.717 as a potential antimalarial agent. Other compounds (compounds 34 and 35) also showed moderate activity against a CQ-sensitive strain (NF54) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum.

National Research Foundation (NRF)