Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

Abstract

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum. Interestingly, 7e, a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.

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].…”

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

“…Mathew and co-workers have performed the virtual screening of 400 molecules from the malaria box library using 3D pharmacophore to reveal TCMDC-140230 as a potent antimalaria agent, targeting the methyl-D-erthyritol-4-phosphate pathway (MEP) pathway. [57] During the synthesis of four stereoisomers of TCMDC-140230, the hydrochloride salt of indole derivative 22 was obtained as a minor by-product having potent activity against P. falciparum (EC 50 of 108 nM) and orally potent through the in vivo mouse model of malaria in a dose of 40 mg/kg. Herein, the (1R,3S)-stereochemistry, 2',4'-dichloro substituents, and 3-carboxamides were found essential for antimalarial effects.…”

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

“…Pf ATPase4 inhibitor antimalarial candidate cipargamin 2 ), we thought it would be worthwhile to revisit compounds within the original 20K compound hit set of the Malaria Box, to see if related structures were present. In our previous paper, we described how similarity searching of the GSK portion of the hit set (∼13K compounds) led to the discovery of an orally active β-carboline antimalarial . In this report we focused on the Novartis portion of the hit set (5K compounds) , and identified tetrahydro-β-carboline GNF-Pf-5009, designated as (±)- 3b in Figure .…”

“…In our previous paper, we described how similarity searching of the GSK portion of the hit set (∼13K compounds) led to the discovery of an orally active β-carboline antimalarial. 14 In this report we focused on the Novartis portion of the hit set (5K compounds) 15,16 and identified tetrahydro-β-carboline GNF-Pf-5009, designated as (±)-3b in Figure 2. Note that within the structure−activity relationship (SAR) we had established for 1, 8,10,11 (±)-3b appeared to have a number of undesirable features as an Pf IspD inhibitor, namely the absence of a 3carboxy group, lack of a halogen at 2′, and N2-substitution.…”