Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides

Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are active against numerous mycobacteria including Mycobacterium tuberculosis and Mycobacterium abscessus. As peptides, they are rapidly degraded in human and murine microsomal suspensions. Adding small substituents to the residues adjacent to the amide bonds, in particular at the anilide bond, results in increased stability.

Abstract

Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 novel AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma-stable and non-cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.

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