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

23 Feb 2022

Mathew J, Ding S, Kunz KA, Stacy EE, Butler JH, Haney RS, Merino EF, Butschek GJ, Rizopoulos Z, Totrov M, Cassera MB, Carlier PR

ACS Medicinal Chemistry Letters
PMID: 35300096

Doi: 10.1021/acsmedchemlett.1c00663

Photo: Gerasimov_iStock

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.

Please visit the PubMed website to view the full article.