Synthesis and Characterization of Phenylalanine Amides Active against and Other Mycobacteria.

α-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2)--(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against (MIC 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 configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against , , , and . The sulfone derivatives exhibit lower MIC values (: 0.78 μM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of at 12.5 μM), while they are not cytotoxic against mammalian cell lines.