Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, Halle (Saale) 06120, Germany.
Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, New Jersey 07110, United States.
J Med Chem. 2023 Apr 13;66(7):5079-5098. doi: 10.1021/acs.jmedchem.3c00009. Epub 2023 Mar 31.
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.
α-2-噻吩甲酰基-d-苯丙氨酸-2-吗啉基苯胺[MMV688845，病原体框；疟疾药物倡议；IUPAC：（2）-（1-（（2-吗啉基）氨基）-1-氧代-3-苯基丙-2-基）噻吩-2-甲酰胺）]是一种有效化合物，对（MIC6.25-12.5μM）和其他分枝杆菌具有活性。本工作通过引入噻唑啉基部分来对 MMV688845 进行衍生化，并制备了相应的砜和亚砜。通过 X 射线晶体学证实了三个类似物的分子结构。通过手性 HPLC 对一个代表性化合物证明了在合成过程中保持关键构型的一致性。所有类似物均在 MIC 测定中针对、、、和进行了表征。砜衍生物表现出较低的 MIC 值（：0.78μM），而亚砜的水溶解度高于有效化合物。最有效的衍生物具有杀菌活性（在 12.5μM 时，对 99%的失活），而对哺乳动物细胞系无细胞毒性。
