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

Abstract

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.

Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria

“…Molecular docking is one of the most widely used computational approaches in the design of structure-based drugs [ 67 , 68 ]. This approach can be used both to identify the correct conformation of the ligand within the target binding pocket and to estimate the interaction energy between a target and a ligand [ 69 , 70 ].…”

Comparative enantioseparation of chiral 4,4’-bipyridine derivatives on coated and immobilized amylose-based chiral stationary phases

“…The enantiomer elution order (EEO) was determined by injecting enantiomers of known absolute configuration. Pure enantiomers of compounds 1-7 were obtained by HPLC enantioseparation and their absolute configuration was assigned on the basis of X-ray diffraction or by comparison of theoretical/experimental electronic circular dichroism spectra, as previously described [16,20].…”

“…Moreover, compounds 1-4 have applicative interest as they exhibited promising activity as inhibitors of transthyretin (TTR) misfolding, which is implicated in the TTR amyloidosis diseases [16], the M-enantiomer showing different activity with respect to the P-enantiomer (Fig. 2b).…”

Modulation of the Mechanisms Driving Transthyretin Amyloidosis

“…The most relevant compounds are listed in Table 1 and will be discussed in the following sections. In the recent years, computational studies, such as molecular dynamics (MD) simulations, molecular docking and quantitative structural-activity relationships (SAR) have been used as complement of experimental approaches to better understand TTR monomer misfolding mechanismsdriving TTR amyloidogenesis (Zhou et al, 2019), as well as the binding of small molecules to TTR (Dessi et al, 2020). Indeed, these in silico experiments have been essential to obtain a more detailed information about structural changes in biomolecules and, have been used to determine the structural dynamics of TTR (Ortore and Martinelli, 2012;Zhao and Lei, 2014), which in turn will be particularly relevant to the development of more targeted and effective therapies for the treatment of ATTR amyloidosis.…”