β-Carboline Derivatives Tackling Malaria: Biological Evaluation and Docking Analysis

Abstract

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 (1<i>R</i>,3<i>S</i>)-methyl 1-(benzo[<i>d</i>][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1<i>H</i>-pyrido[3,4-<i>b</i>]indole-3-carboxylate (<b>9a</b>) alone <i>in vitro</i> against <i>Plasmodium falciparum</i> and <i>in vivo</i> in combination therapy with the standard drug artesunate against <i>Plasmodium berghei</i>. Compound <b>9a</b> inhibited both 3D7 and RKL-9 strains of <i>P. falciparum</i> 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 <i>in vivo</i> antimalarial activity (median effective dose (ED₅₀) = 27.74 mg/kg) in monotherapy. The combination of <b>9a</b> (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 <b>9a</b> as a potential antimalarial candidate.