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

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 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.

Broad-Spectrum In Vitro Activity of Nα-Aroyl-N-Aryl-Phenylalanine Amides against Non-Tuberculous Mycobacteria and Comparative Analysis of RNA Polymerases

“…We also wanted to determine the influence of 5-fluoro substitution in para-position to the morpholine moiety (compounds 4 to 6). Compounds 8 to 10 showed high anti-NTM activity and have been synthesized and tested in a previous study with the aim to improve the stability of the compound class by additional sterical hindrance of the amide bonds [32]. The molecular structures of the tested compounds are given in Scheme 1 while their previously published activities against NTM can be found in Table 1.…”

“…The compounds selected for assessment against the strains described in this study were synthesized and characterized as described previously [25,32]. The selection of the test set considered their activity against previously tested mycobacteria, as well as diverse structural features that could affect the activity against different NTM species Compounds 1 to 7 were synthesized during a detailed SAR study that varied the ring systems of the chemical scaffold in the search for better activity against NTM.…”