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Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines
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Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides

Markus Lang1, Uday S Ganapathy2, Lea Mann1

  • 1Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle (Saale), Germany.

Chemmedchem
|February 8, 2024
PubMed

Insights

Novel Nα-aroyl-N-aryl-phenylalanine amides (AAPs) show improved stability against degradation. Shielding amide bonds with fluorine enhances antimycobacterial activity and bioavailability for treating tuberculosis.

Area of Science:

  • Medicinal Chemistry
  • Microbiology
  • Drug Discovery

Background:

  • Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are investigated as RNA polymerase inhibitors.
  • AAPs exhibit activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria.
  • Rapid degradation of AAPs in microsomal suspensions indicates a need to overcome hepatic metabolism for in vivo efficacy.

Purpose of the Study:

  • To synthesize novel AAP analogs with enhanced metabolic stability.
  • To evaluate the antimycobacterial activity of these analogs.
  • To explore the potential of steric shielding to improve AAP stability and bioavailability.

Main Methods:

  • Synthesis of 16 novel AAP analogs with methyl or fluoro substituents near amide bonds.
  • Assessment of microsomal and plasma stability.
  • Determination of antimycobacterial activity against M. tuberculosis, M. abscessus, M. avium, and M. intracellulare.
  • Evaluation of cytotoxicity.

Main Results:

  • Several AAP derivatives demonstrated improved microsomal stability.
  • Synthesized analogs were stable in plasma and non-cytotoxic.
  • Metabolic stability data correlated with antimycobacterial activity.
  • Fluorine substitution showed potential for enhancing stability and bioavailability.

Conclusions:

  • Steric shielding of anilide groups, particularly with fluorine, can improve AAP metabolic stability.
  • Enhanced stability is crucial for improving the in vivo effectiveness of AAPs against mycobacterial infections.
  • This strategy holds promise for developing more potent and bioavailable antimycobacterial agents.
Keywords:
AAPsMycobacterium abscessusNTMPhenylalanine amidesRNA polymeraseTuberculosismicrosomal stability

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