Substituent effect on the reductive N-dearylation of 3-(indol-1-yl)-1,2-benzisoxazoles by rat liver microsomes.
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.
Tschirret-Guth
Richard A
RA
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA. richard_tschirretguth@merck.com
Wood
Harold B
HB
D000388:Air; D000578:Amidines / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism / Q000493:pharmacokinetics; D002623:Chemistry Techniques, Analytical; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004583:Electrons; D007211:Indoles / Q000032:analysis / Q000378:metabolism*; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D007654:Ketoconazole / Q000378:metabolism / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D009249:NADP / Q000037:antagonists & inhibitors / Q000378:metabolism; D010080:Oxazoles / Q000032:analysis / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013329:Structure-Activity Relationship
D000578:Amidines; D007211:Indoles; D007555:Isoxazoles; D010080:Oxazoles; D009249:NADP; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole