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.
Jopaul Mathew, Sha Ding, Kevin A Kunz, Emily E Stacy, Joshua H Butler, Reagan S Haney, Emilio F Merino, Grant J Butschek, Zaira Rizopoulos, Maxim Totrov, Maria B Cassera, Paul R Carlier. ACS Med Chem Lett. 2022 Feb 23;13(3):365-370. doi: 10.1021/acsmedchemlett.1c00663.