Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria

  • J Med Chem. 2023 Apr 13;66(7):5079-5098. doi: 10.1021/acs.jmedchem.3c00009.
Markus Lang  1 ,  Uday S Ganapathy  2 ,  Lea Mann  1 ,  Rana Abdelaziz  1 ,  Rüdiger W Seidel  1 ,  Richard Goddard  3 ,  Ilaria Sequenzia  1 ,  Sophie Hoenke  4 ,  Philipp Schulze  3 ,  Wassihun Wedajo Aragaw  2 ,  René Csuk  4 ,  Thomas Dick  2  5  6 ,  Adrian Richter  1
Affiliations
  • 1. Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, Halle (Saale) 06120, Germany.
  • 2. Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, New Jersey 07110, United States.
  • 3. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, Mülheim an der Ruhr 45470, Germany.
  • 4. Institut für Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle (Saale) 06120, Germany.
  • 5. Department of Medical Sciences, Hackensack Meridian School of Medicine, 123 Metro Blvd, Nutley, New Jersey 07110, United States.
  • 6. Department of Microbiology and Immunology, Georgetown University, 3900 Reservoir Road, N.W., Washington, District of Columbia 20007, United States.
PMID: 37001025 DOI: 10.1021/acs.jmedchem.3c00009
Abstract

Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2R)-N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC90 6.25-12.5 μM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential R configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against M. abscessus, Mycobacterium intracellulare, Mycobacterium smegmatis, and Mycobacterium Tuberculosis. The sulfone derivatives exhibit lower MIC90 values (M. abscessus: 0.78 μM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of M. abscessus at 12.5 μM), while they are not cytotoxic against mammalian cell lines.