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

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-beta-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.

Automated summary

Virtual ligand screening using a pharmacophore derived from antimalarial MMV008138 led to the identification of TCMDC-140230 as a compound worth exploring. However, none of the four stereoisomers synthesized showed potent inhibition of Plasmodium falciparum growth, while a minor byproduct 7e exhibited strong in vitro antimalarial activity and was orally efficacious in an in vivo mouse model of malaria.