RT Journal Article
SR Electronic
T1 SUBSTITUENT EFFECT ON THE REDUCTIVE <em>N-</em>DEARYLATION OF
 3-(INDOL-1-YL)-1,2-BENZISOXAZOLES BY RAT LIVER MICROSOMES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 999
OP 1004
DO 10.1124/dmd.31.8.999
VO 31
IS 8
A1 Richard A. Tschirret-Guth
A1 Harold B. Wood
YR 2003
UL http://dmd.aspetjournals.org/content/31/8/999.abstract
AB The reductive metabolism of a series of 3-(indol-1-yl)-1,2-benzisoxazoles was examined in vitro using rat liver microsomes. 3-(Indol-1-yl)-1,2-benzisoxazole was reduced to the corresponding amidine (resulting from N–O bond cleavage) under anaerobic conditions. The reaction required viable microsomes and NADPH and was inhibited by carbon monoxide, air, and ketoconazole, suggesting the involvement of cytochrome P450 enzymes. The amidine was subsequently nonenzymatically hydrolyzed to 1-salicylindole, which in turn was hydrolyzed to indole. Addition of electron-withdrawing substituents (Cl-, MeSO2-) at the 6-position of the benzisoxazole ring resulted in a significant increase in the rate of substrate reduction. Introduction of electron-withdrawing substituents on the indole ring likewise increased the rate of substrate consumption but caused a substituent-dependent shift of the site of bond cleavage from the 1,2-isoxazole N–O bond to the C–N bond linking the 1,2-benzisoxazole to the indole moiety. In the case of 3-(2-chloro-3-methanesulfoxylindol-1-yl)-1,2-benzisoxazole, C–N bond cleavage was nearly quantitative, and products resulting from N–O bond reduction were not observed. The overall rates of 3-(indol-1-yl)-1,2-benzisoxazoles reduction were found to be substrate concentration-dependent and observed Michaelis-Menten-type behavior. The apparent Vmax of substrate reduction by rat liver microsomes correlated negatively with the free energy of the lowest unoccupied molecular orbitals (ELUMO) calculated semiempirically using a parameterized model 3 (PM3), and suggested that the initial electron transfer was rate-determining and that the ELUMO could be used as an indication of the susceptibility of 1,2-isoxazoles to undergo reductive metabolism. The American Society for Pharmacology and Experimental Therapeutics