2. Academic Validation
  3. Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria

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

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.

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