Iboga-Indole Alkaloids as Potential Plasmodial Inhibitors: Identification, Biosynthesis, and Molecular Docking...

A previously undescribed iboga-indole alkaloid, voacamine A (1), and the known alkaloids, voacamine (2), voacorine (3), and voacangine (4) were isolated from the stem bark of Voacanga africana. The structures of the alkaloids were established by one- and two-dimensional nuclear magnetic resonance analyses as well as by comparison with published data. The antiplasmodial activity of the alkaloids was assessed on a chloroquine-sensitive 3D7 Plasmodium falciparum (Pf3D7) strain, and the half-maximal inhibitory concentration (IC₅₀) values were determined. Alkaloids 2 and 3 showed good in vitro antiplasmodial activity with IC₅₀ values of 5.734 ± 1.365 and 5.319 ± 2.206 µg/mL, respectively, at the concentration tested. A plausible biogenetic pathway of the bisindole alkaloids has been proposed. Protein-ligand co-folding was used to generate protein-ligand complexes for the pfATP6 protein target and the isolated alkaloids. The stability of the modelled complexes was evaluated using molecular dynamics simulation. Scoring metrics of the generated complexes coupled to molecular mechanics generalized-born solvation rescoring of the modelled ligand poses were employed to explain the antimalarial structure-activity relationship for the investigated compounds. Alkaloids 2 and 3 can be considered as possible scaffolds for designing new antiplasmodial lead compounds.