Isolation, Structure, Synthesis and Cytotoxicity of an Unprecedented Flupirtine Dimer

Abstract

A previously unknown dimer of the well-established analgesic flupirtine has been found, and its structure was revealed by ESI-MS, NMR spectroscopy and an independent synthesis. Thus, starting from 2-amino-6-chloro-3-nitro-pyridine the target compound was obtained in a four-step synthesis. Key-step of this synthesis is a nickel-mediated aryl-aryl coupling. The dimer 4 did not show any cytotoxicity, and its IC 50 values were > 30 µm for all six human cancer cell lines and mouse fibroblasts used in this study.

Exploring the molecular determinants for subtype-selectivity of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid analogs as betaine/GABA transporter 1 (BGT1) substrate-inhibitors

“…To avoid polyalkylation, the 2-amino alkylated analog 10 was achieved by a coupling between the commercially available ethyl 2-chloropyrimidine-5-carboxylate 31 and 2-phenylethan-1-amine to give 32 (Fig. 2 a) 40 . Catalytic hydrogenation ( 33 ), followed by hydrolysis under acidic conditions, afforded the target compound 10 .…”

Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity

“…We also wanted to investigate whether electron‐withdrawing substituents at position 5 of the pyridine ring can influence the biological activity or toxicity relative to 64 . Therefore, bromination was performed with N ‐bromosuccinimide and ammonium chloride as described by Csuk et al . However, instead of using the nitro precursor 17 , we tried to directly brominate compound 36 (Scheme ).…”