Increasing resistance to presently available antimalarial drugs urges the need to look for new promising compounds. The β-carboline moiety, present in several biologically active natural products and drugs, is an important scaffold for antimalarial drug discovery. The present study explores the antimalarial activity of a β-carboline derivative (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) alone in vitro against Plasmodium falciparum and in vivo in combination therapy with the standard drug artesunate against Plasmodium berghei. Compound 9a inhibited both 3D7 and RKL-9 strains of P. falciparum with half-maximal inhibitory concentration (IC50) < 1 μg/mL, respectively. The compound was nontoxic (50% cytotoxic concentration (CC50) > 640 μg/mL) to normal dermal fibroblasts. Selectivity index was >10 against both the strains. The compound exhibited considerable in vivo antimalarial activity (median effective dose (ED50) = 27.74 mg/kg) in monotherapy. The combination of 9a (100 mg/kg) and artesunate (50 mg/kg) resulted in 99.69% chemosuppression on day 5 along with a mean survival time of 25.8 ± 4.91 days with complete parasite clearance. Biochemical studies indicated the safety of the HIT compound to hepatic and renal functions of mice. Molecular docking also highlighted the suitability of 9a as a potential antimalarial candidate.
Copyright © 2020 American Chemical Society.