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The 3,3&prime, 5,5&prime, tetrachloro-2-iodo-4,4&prime, 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&prime, tetrachloro-2-iodo-2&prime, substituted-4,4&prime, 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&prime, substituent. The corresponding racemates, along with other five chiral 4,4&prime, 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&prime, bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3&prime, tetrachloro-2&prime, (4-hydroxyphenyl)-2-iodo-4,4&prime, bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4&prime, 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&prime, bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

Thyroid hormones are well known halogen bond (XB) donors as shown by short I···O contacts that underlie the selective binding of hormone thyroxine (T4) to transthyretin (TTR).[1] This protein is composed of four subunits, which are organized into a homotetrameric quaternary structure with two dimer-dimer interfaces.Dissociation of the native tetramer and subsequent aggregation to form insoluble amyloid fibrils are involved in several TTR amyloidosis (ATTR) diseases. Over the past decade, it was observed that T4 and other small molecules could inhibit the tetramer dissociation, and therefore be efficacious against ATTR diseases.[1] However, currently, these diseases still lack an effective therapy. On this basis, we describe herein the development of new atropisomeric iodinated 4,4'-bipyridines (IBPYs)[2] as TTR misfolding inhibitors. In particular, a docking study was performed in order to inspect interactions and binding modes of the IBPYs into the TTR. The (M)-2-iodo-4,4'-bipyridyl substructure has been identified as suitable for developing the new TTR stabilizers (Figure b). Interestingly, in this case, a XB was observed between the 2-iodine of IBPY and the side chain of Ser117' with distance and angle values in accord with what is defined as XB biomolecular contacts (penetration of the van der Waals atomic spheres -2.8%, angles: C-I···O = 149.34° and I···O-C = 111.85°).[3] References [1] Johnson, S. M., Wiseman, R. L., Sekijima, Y., Green, N. S., Adamski-Weiner, S. L., Kelly, J. W., Acc. Chem. Res. 2005, 38, 911-921. [2] (a) Mamane, V., Aubert, E., Peluso, P., Cossu, S., J. Org. Chem. 2013, 78, 7683-7689; (b) Mamane, V., Peluso, P., Aubert, E., Cossu, S., Pale, P., J. Org. Chem. 2016, 81, 4576-4587. [3] Ho, P. S., Top. Curr. Chem. 2015, 358, 241-276. Acknowledgement: This work has been supported by Università Ca' Foscari di Venezia, Italy (DSMN, ADIR funds). V. M. thanks the International Center Frontier Research in Chemistry (icFRC) and the Laboratory of Excellence for Complex System Chemistry (LabEx CSC).