The difficulty of developing an efficient
malaria vaccine along with increasing spread of multidrug resistant strain of Plasmodium falciparum to the available
antimalarial drugs poses the need to discover safe and efficacious
antimalarial drugs to control
malaria. An alternative strategy is to synthesize compounds possessing structures similar to the active natural products or marketed drugs. Several biologically active natural products and drugs contain β-
carboline moiety. In the present study, few selected β-
carboline derivatives have been synthesized and tested for their in vitro and in vivo antiplasmodial activity against the rodent
malaria parasite Plasmodium berghei (NK-65). The designed analogs exhibited considerable in vitro
antimalarial activity. Two compounds (1R,3S)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]
indole-3-carboxylate (9a) and (1R,3S)-methyl 1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]
indole-3-carboxylate (9b) were further selected for in vivo studies. Both the lead compounds (9a and 9b) were observed to be safe for
oral administration. The therapeutic effective dose (ED50) for 9a and 9b were determined and in the animal model, 9a (at 50 mg/kg dose) exhibited better activity in terms of parasite clearance and enhancement of host survival. Biochemical investigations also point toward the safety of the compound to the hepatic and renal functions of the rodent host. Further studies are underway to explore its activity alone as well as in combination
therapy with
artesunate against the human
malaria parasite P. falciparum.