Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

The 3,3 ',5,5 '-tetrachloro-2-iodo-4,4 '-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ',5,5 '-tetrachloro-2-iodo-2 '-substituted-4,4 '- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2 '-substituent. The corresponding racemates, along with other five chiral 4,4 '-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4 '-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ',5,5 '-tetrachloro-2 '-(4-hydroxyphenyl)-2-iodo-4,4 '-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4 '-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4 '-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.