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

24 Feb 2022

Almolhim H, Ding S, Butler JH, Bremers EK, Butschek GJ, Slebodnick C, Merino EF, Rizopoulos Z, Totrov M, Cassera MB, Carlier PR

ACS Medicinal Chemistry Letters
PMID: 35300082

Doi: 10.1021/acsmedchemlett.1c00697

Photo: Qvist_Shutterstock

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.

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