Production of a novel dimeric metabolite of primaquine by Streptomyces rimosus

Abstract

Primaquine, an 8-amino-6-methoxyquinoline antimalarial agent, was subjected to metabolic studies with microorganisms. Streptomyces rimosus converted primaquine to the previously reported N-acetyl derivative. Continued incubation of S. rimosus resulted in the formation of a minor dimeric metabolite. The structure of the minor dimeric metabolite was proposed based primarily on its spectral data (1H and 13C nuclear magnetic resonance spectra and mass spectrum). The proposed structure of the metabolite was confirmed by synthesis of the dimer by treatment of primaquine-N-acetate with potassium ferrocyanide in a biphasic chloroform-aqueous sodium bicarbonate system with a phase-transfer catalyst. Since (±)-primaquine was used for both the microbial transformation and synthesis, a diastereomeric mixture of symmetrical dimers was formed in each case. The metabolite sample was identical to the synthetic sample, as shown by direct comparison (thin-layer chromatography, co-thin-layer chromatography, high pressure liquid chromatography, co-high-pressure liquid chromatography, 1H nuclear magnetic resonance spectra, and mass spectrum).