Cytochrome P450-mediated metabolism of antimycobacterial Nα-Aroyl-N-aryl-phenylalanine amides

Abstract

Nα-Aroyl-N-aryl-phenylalanine amides (AAPs) are a class of antimycobacterial substances that inhibit the RNA polymerase and are effective against various pathogenic and opportunistic mycobacteria, including Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium avium. Further development of these promising compounds, however, has been hindered by their low microsomal stability, leading to insufficient bioavailability. The present study investigates the mechanism by which microsomal enzymes metabolically degrade AAPs and identifies the resulting metabolites using LC-MS/MS. Rapid oxidation of the ortho-phenylenediamine structure, present in various substances in this class, plays a key role in this process. Additionally, we demonstrated in vitro and in vivo that cytochrome P450 enzyme inhibitors significantly slow the degradation of AAPs. Identification of metabolites will inform further chemical modification of AAPs to achieve metabolic stability.