Synthesis and Evaluation of Antiplasmodial Efficacy of β-Carboline Derivatives against Murine Malaria

Abstract

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.

The antimalarial activity of indole alkaloids and hybrids

“…[ 69 ] The β‐carboline derivatives 29a , b exhibited 71.79% and 86.17% inhibition of P. berghei schizont maturation respectively at a concentration of 5 µg/ml, whereas the reference chloroquine exhibited 90.66% inhibition at 10 µg/ml. [ 70 ] These two hybrids did not cause any deaths and behavioral changes at a dose of >2.5 g/kg in the in vivo acute toxicity evaluation, suggesting their excellent safety profile. In the P. berghei ‐infected mouse model, compound 29a (50 mg/kg, orally) exhibited promising activity in terms of parasite clearance (suppression of 88.93% and 97.57% parasitemia at Days 5 and 28, respectively, while chloroquine group was 98.32% and 100% at a dose of 10 mg/kg) and enhancement of host survival (mean survival time: 23.4 days, while the untreated group was 8.2 days).…”

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

“…The acute toxicity studies of 9a (LD 50 > 4 g/kg) indicated its toxicological safety for oral administration at higher doses. 22 The compound was further evaluated for its antimalarial potential in vivo in monotherapy to confirm our previous findings, and lower doses were also tested to determine the median effective dose (ED 50 ) and its efficacy in combination therapy with artesunate. Rodent malaria parasite species are well-established experimental models for testing the efficacy of novel drug candidates.…”

Synthesis and Investigation of Tetrahydro-β-carboline Derivatives as Inhibitors of Plant Pathogenic Fungi

“…The incorporation of aromatic substituents at the C1 position was reported to improve the activity, and the presence of the carbonyl group at the C3 position was also found to be important for the enhancement of activity [ 1 , 11 , 21 , 27 , 35 ]. Thus, we designed the preparation of the substituted THβCs via the efficient Pictet-Spengler reaction with tryptamine ( 1a ), L -tryptophan methyl ester ( 1b ), and appropriate aldehydes in acid media ( Scheme 1 ).…”

“…Moreover, THβC with an eight-carbon linear chain at the C1 position, (1 R ,3 S )-methyl 1-octyl-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b ]indole-3-carboxylate, showed in vitro antifungal activity against Candida glabrata with disruption of the membranes of fungal cells by increased asymmetry and decomposition of the cell surface [ 20 ]. Thus, the pharmaceutically important β-carboline-based natural products are advantageous for medicinal and organic research, while 1,3 disubstituted THβCs are reported to be synthetically and biologically interesting analogs [ 35 ]. Currently, Tadalafil, the hydantoin fused at the nitrogen and C3 of THβC with a substituent at C1 is clinically used to treatment erectile dysfunction under the brand name Cialis [ 36 ] and is also used for pulmonary arterial hypertension treatment under the brand name Adcirca [ 37 ].…”