Abstract:
Malaria is ranked seventh among the leading causes of death in sub-Saharan Africa. The major setback to treatment of malaria has been the emergence of parasite resistance to antimalarial drugs especially chloroquine (CQ) which was once held as a gold standard for malaria treatment. Research has shown that compounds referred to as chemosensitizers are capable of reversing resistance to CQ and CQ-like molecules. Thus in keeping with the need to save the limited arsenal of antimalarial drugs and to restore the usefulness of CQ and CQ-like molecules, a rational drug design approach to synthesize a novel antimalarial hybrid drug by covalently linking a quinoline pharmacophore to a chemosensitizer pharmacophore, is presented in this study. A linear synthetic route was used to synthesize the quinoline-chemosensitizer molecule making use of ethylene diamine as the linker. This was followed by in vitro evaluation of the molecule for antiplasmodial activity using 3D7 (CQ sensitive) and W2 (multidrug resistant) strains of P. falciparum and drug cytotoxicity to Vero cells by the MTT assay. The hybrid molecule was then re-evaluated against lumefantrine resistant (LUM-R) P. berghei parasites in mice using the 4-day suppressive test. The successfully synthesised hybrid molecule exhibited activity of 0.66 ± 0.06 µg/ml in 3D7 and 0.62 ± 0.01 µg/ml in W2 strain which was higher than that of the individual precursor molecules (4,7-dichloroquinoline, probenecid) and the combination. There was no cytotoxicity exhibited by the compound on Vero cells. Additionally, treatment with the hybrid compound was not effective in the mice infected with lumefantrine (LM) resistant P. berghei when compared to mice treated with LM. The results successfully validate the concept of utilizing a hybrid molecule to combine antiplasmodial activity and resistance reversal activity effective against P. falciparum and reflect the likelihood of resistance reversal capability of probenecid in vitro as reported previously. However, further structural modification could be considered to improve on the activity of the molecule in vivo. An active quinoline pharmacophore such as piperaquine could be used to ensure antiplasmodial activity and an active reversal agent that would allow for resistance reversal activity.
