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

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.