Oxidative metabolism of quinazoline insecticide fenazaquin by Aspergillus niger

Abstract

Fenazaquin (4-(2-(4-t-butylphenyl)ethoxy)quinazoline) is a quinazoline insecticide, which contains a rare pesticidal toxophore, quinazoline. Its metabolic fate in animals and plants was previously reported. However, the microbial metabolism of the compound has never been studied. Microbial transformation is an important research area for the investigation of environmental safety issues of pesticides. Aspergillus niger was selected as a model soil fungus since it is ubiquitous in agricultural soils, with extensive genetic studies undertaken. Fenazaquin was rapidly metabolized by A. niger (half-life, t1/2 = 0.6 day). 4-Hydroxyquinazoline and 4-t-butylphenethyl alcohol were identified as major metabolites from the cultures. Fenazaquin was also rapidly transformed into the same metabolites (t1/2 = 0.1–0.5 day) under chemical oxidation (m-chloroperoxybenzoic acid). Among the several metabolic inhibitors, flavin-dependent mono-oxygenase inhibitor, methimazole yielded no inhibitory activity (t1/2 = 1.6 day). Several cytochrome P450 inhibitors including piperonyl butoxide, ketoconazole, and myclobutanil were also tested. Piperonyl butoxide strongly reduced fenazaquin metabolism (t1/2 = 58.7 days). However, ketoconazole and myclobutanil showed no activity even at fungi-toxic concentrations (t1/2 = 1.2–4.3 days) with major metabolites similar to those of control experiments. The results suggest that oxidative metabolism of fenazaquin was catalyzed by specific cytochrome P450s, which are insensitive to azole fungicides. In addition, piperonyl butoxide was found to be one of the most promising synergists of pesticides, through cytochrome P450 inhibition.