The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138, 1). To search for new antimalarial compounds, a generalized 3D pharmacophore derived from 1 was developed. Using this pharmacophore, a virtual ligand screen of the 5K compound Novartis antimalarial hit set was performed, revealing a stereochemically-undefined N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)-2). 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, by resolution of the corresponding amine precursors prior to N-acylation (configuration confirmed by X-ray crystallography, demonstrated the pharmacological superiority of (R)-2. (R)-2 proved to be potent against the drug-resistant Dd2 strain, with EC50 = 107 ±10 nM; Interestingly, (S)-2 shows a biphasic concentration response, leading to significantly higher EC95 values for parasite clearance. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure−activity relationship. Note that (R)-2 has low toxicity to three mammalian cell-lines (CC50/EC50 ratios ≥ 100) and has a different mechanism of antimalarial action than 1. Despite two Ro5 violations (MW and Log D), in vitro ADME-Tox and rat PK analysis of (R)-2 were performed, and most indicators were favorable. Ultimately (R)-2 was tested in Plasmodium berghei-infected mice; no efficacy was seen after dosing at 40 mg/kg/day. Unfavorable physicochemical properties may be responsible for the lack of oral efficacy.

Synthesis of enantiopure antimalarial N2-acyl tetrahydro-β-carbolines

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