3-Amino-5-phenoxythiophenes:  Syntheses and Structure−Function Studies of a Novel Class of Inhibitors of Cellular l-Triiodothyronine Uptake

A series of substituted 3-amino-5-phenoxythiophenes was synthesized starting from malodinitrile and carbon disulfide. The resulting dicyanoketenedithiolate reacts via Thorpe−Dieckmann cyclization with halogen methanes bearing electron-withdrawing groups to give thiophene-2-thiolates, which can be transformed into 3-amino-5-(methylsulfonyl)thiophene-4-carbonitriles. Replacement of the methylsulfonyl groups by substituted phenolates provides the substituted 3-amino-5-phenoxythiophenes. Some of the derivatives show a considerable inhibitory potency for the l-T3 uptake in inhibition studies on human HepG2 hepatoma cells with maximum values of about 60% at a dose of 10-5 M for the most potent 2-benzoyl derivatives. The structure of the phenoxythiophenes fits well into a general concept derived for other classes of l-T3 uptake inhibitors, which postulates an angular and perpendicular orientation of the ring systems in these compounds as a prerequisite for an inhibitory potency. Docking studies for the phenoxythiophenes with transthyretin as a receptor model show their preferred attack at the l-T4/l-T3 binding channel.