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Journal Article

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

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Goddard,  Richard
Service Department Lehmann (EMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Schulze,  Philipp
Service Department Schulze (GC, HPLC), Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Lang, M., Ganapathy, U. S., Mann, L., Abdelaziz, R., Seidel, R. W., Goddard, R., et al. (2023). Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria. Journal of Medicinal Chemistry, 66(7), 5079-5098. doi:10.1021/acs.jmedchem.3c00009.


Cite as: https://hdl.handle.net/21.11116/0000-000D-068B-0
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.