Synthesis and antimalarial activities of a chloroquinoline-barakol derivative

The study reported in this dissertation aimed at developing novel potential antimalarial compounds by combining the natural product, barakol (24) and 4,7-dichloroquinoline (52) and evaluating its antimalarial activities. The chloroquinoline barakol-derivative, 4-(2-(7-chloroquinolin-4-ylamino)ethyl)-2,5-dimethylpyrano [2,3,4-ij]isoquinolin-8-(4H)-one (23) was successfully synthesized and its antimalarial activities tested in vitro. Compound 24 which was isolated in 0.3% yield as yellow needle shaped crystals from fresh leaves of Cassia siamea was stirred with concentrated HCl in methanol yielding 78% of anhydrobarakol chloride (29). Commercially available 4,7-dichloroquinoline (52) was refluxed with ethane-1,2-diamine to give 42% yield of N-(2-aminoethyl)-7-chloroquinolin-4-amine (51). Precursors 51 and 29 on refluxing in methanol in the presence of pyridine (weak base), gave the target compound 23 in 52% yield. The newly synthesized compound 23 was evaluated for antimalarial activities in vitro (using infected human blood) whereby Plasmodium falciparum chloroquine sensitivity (3D7) strain growth was inhibited with IC50 value of 0.51 µM. The cytotoxicity of 23 and 24 were evaluated using brine shrimp (Artemia salina. Leach) larvae, where LC50 of maximum 0.79 mM and 13.36 mM for 23 and 24 respectively were obtained. Additionally, toxicity of compound 23 was assessed by HeLa cells and indicated 80% viability, a significant indicator of safe antimalarial candidate. The findings of this study call for more efforts to be directed towards extended synthesis and testing of other chloroquinoline–barakol derivatives as part of efforts of drug discovery and development particularly antimalarial therapeutics.