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

  • ACS Med Chem Lett. 2022 Feb 23;13(3):365-370. doi: 10.1021/acsmedchemlett.1c00663.
Jopaul Mathew  1 ,  Sha Ding  1 ,  Kevin A Kunz  1 ,  Emily E Stacy  1 ,  Joshua H Butler  2 ,  Reagan S Haney  2 ,  Emilio F Merino  2 ,  Grant J Butschek  2 ,  Zaira Rizopoulos  3 ,  Maxim Totrov  4 ,  Maria B Cassera  2 ,  Paul R Carlier  1
Affiliations
  • 1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, 1040 Drillfield Drive, Blacksburg, Virginia 24061, United States.
  • 2. Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases, University of Georgia, 120 Green Street, Athens, Georgia 30602, United States.
  • 3. Medicines for Malaria Venture, 1215 Geneva, Switzerland.
  • 4. Molsoft LLC, 11999 Sorrento Valley Road, San Diego, California 92121, United States.
PMID: 35300096 DOI: 10.1021/acsmedchemlett.1c00663
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.

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