Biotransformation and molecular docking of cyazofamid by human liver microsomes and cDNA-expressed human recombinant P450s

The purpose of this study was to understand the formation of metabolites from the metabolic reaction of cyazofamid with human liver microsomes. Human liver microsomal incubation of cyazofamid in the presence of NADPH produced one metabolite, 4-chloro-2-cyano-5-(4-(hydroxymethyl)phenyl)N,N-dimethyl-1H-imidazole-1-sulfonamide (CCHS). An incubation study using cDNA-expressed human recombinant P450s (rCYPs) demonstrated that cyazofamid-derived CCHS is mediated by CYP2B6, 2C9, and 2C19 at different reaction rates. The crystal structure of cyazofamid was obtained using single-crystal X-ray diffraction. According to a molecular modeling study of the crystal structure of cyazofamid with the rCYPs 2B6, 2C9, 2C19, and 3A4, the metabolic reactivities (2B6 > 2C19 > 2C9) were well-correlated to the distances between heme irons of CYPs and 4-methylphenyl group of cyazofamid.