Synthesis and Characterization of Phenylalanine Amides Active against <i>Mycobacterium abscessus</i> and Other Mycobacteria
Markus Lang, Uday S. Ganapathy, Lea Mann, Rana Abdelaziz, Rüdiger W. Seidel, Richard Goddard, Ilaria Sequenzia, Sophie Hoenke, Philipp Schulze, Wassihun Wedajo Aragaw, René Csük, Thomas Dick, Adrian Richter
Abstract
N α-2-thiophenoyl- d -phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2 R )- N -(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC 90 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 MIC 90 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.