Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-β-carbolines Are Potent Antimalarials In Vitro

Abstract

The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 (1) and cipargamin (2)). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling 1 drew our attention to N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)-3b). Compound purchase, “analog by catalog”, and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for in vitro efficacy against P. falciparum. Preparation of pure enantiomers demonstrated the pharmacological superiority of (R)-3b. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure–activity relationship. Ultimately (R)-3b was tested in Plasmodium berghei-infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.

Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria

“…Inhibition of PfFNR interrupts the activity of HMB-PP reductase (IspH), consequently reducing the synthesis of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) and their derivatives, leading to the death of the protozoan [51]. These results reinforce the hypothesis that β-carbolines would act by inhibiting the synthesis of isoprenoids in malaria parasites [16,[53][54][55][56].…”

“…Regarding the SI, all compounds showed high selectivity for the parasites (SI > 10) (values ranged from >55 to >196) (Table 2). The antiplasmodial activity of compounds containing the β-carboline scaffold have been reported over the years [16,55,56,60,61]. The reported in vitro antiplasmodial activity of all compounds reaches a recently established set of criteria for antimalarial hits, which includes: knowledge of the structure-activity; an inhibitory concentration half-maximum response (IC 50 ) < 1 µM; and an SI greater than 10-fold against a human cell line [62].…”

“…Despite the known antimalarial activity of quinoline alkaloids, another subclass of indole alkaloids, the β-carbolines, has been highlighted since some studies have demonstrated its efficacy in vitro and in vivo against Plasmodium spp. [16,55,56,60,61,[71][72][73][74]. Some β-carboline derivatives were in vitro active against both sensitive or multiresistant P. falciparum strains, showing low IC 50 and important SI values [71,74].…”

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Almolhim and co‐workers have reported the tetrahydro‐β‐carboline scaffold clubbed with benzofuran ( 10 ) as an anti‐malarial agent against Pf Dd2 strains with EC 50 of 185±22 nM (Figure 5), [47] wherein the benzofuran‐2‐yl amide has been reported to be essential for in vitro activity against P. falciparum . Further, the R ‐isomer of ( 10 ) was found more effective than its S ‐isomer upon pharmacological screening.…”