Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-β-carbolines Are Potent Antimalarials <i>In Vitro</i>
Hanan Almolhim, Sha Ding, Joshua H. Butler, Emily K. Bremers, Grant J. Butschek, Carla Slebodnick, Emilio F. Merino, Zaira Rizopoulos, Maxim Totrov, María B. Cassera, Paul R. Carlier
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.