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

  • ACS Med Chem Lett. 2022 Feb 24;13(3):371-376. doi: 10.1021/acsmedchemlett.1c00697.
Hanan Almolhim  1 ,  Sha Ding  1 ,  Joshua H Butler  2 ,  Emily K Bremers  2 ,  Grant J Butschek  2 ,  Carla Slebodnick  1 ,  Emilio F Merino  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: 35300082 DOI: 10.1021/acsmedchemlett.1c00697
Abstract

The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 (1) and cipargamin (2)). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling 1 drew our attention to N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)-3b). Compound purchase, "analog by catalog", and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for in vitro efficacy against P. falciparum. Preparation of pure enantiomers demonstrated the pharmacological superiority of (R)-3b. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately (R)-3b was tested in Plasmodium berghei-infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.

Products