Polymorphism of an Nα-Aroyl-N-Aryl-Phenylalanine Amide: An X-ray and Electron Diffraction Study

• Published in: MolBank Vol. 2024; no. 3; p. M1851
• Main Authors: Lang, Markus, Goddard, Richard, Patzer, Michael, Ganapathy, Uday S., Dick, Thomas, Richter, Adrian, Seidel, Rüdiger W.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.09.2024
• Subjects: Amides; amino acids; Analysis; antibiotics; Aromatic compounds; Asymmetry; Chemical synthesis; Coupling (molecular); Cyano groups; Diffraction; drug discovery; Electron diffraction; Hydrogen bonds; Identification and classification; Lead compounds; Methods; Molecular structure; mycobacteria; Phenylalanine; Polymorphism; Polymorphism (Crystallography); Properties; Protons; Racemization; RNA polymerase; Structure; Symmetry; Tuberculosis; X-rays; Germany
• ISSN: 1422-8599; 1422-8599
• DOI: 10.3390/M1851

In view of the rise of drug-resistant tuberculosis and difficult-to-treat related diseases caused by non-tuberculous mycobacteria, there is an urgent need for antimycobacterial drug discovery. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as antimycobacterial agents and are subject to lead optimization. The aim of the present study is to evaluate the impact of N-aryl ortho cyano substitution in a lead compound on the crystal and molecular structure and its in vitro activity against Mycobacterium abscessus. The title AAP can be conveniently synthesized from N-Boc-protected d-phenylalanine in two amide coupling steps using a previously established racemization-free method. Two polymorphic forms in the solid-state are described, as discovered by X-ray and electron diffraction. The introduction of a cyano group in the ortho position of the AAP N-aryl ring, however, leads to loss of in vitro activity against M. abscessus subsp. abscessus.