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Synthesis and structure activity relationship of pyridazine-based inhibitors for elucidating the mechanism of amyloid inhibition

Kalhor, H. R ; Sharif University of Technology | 2018

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  1. Type of Document: Article
  2. DOI: 10.1021/acs.chemrestox.8b00210
  3. Publisher: American Chemical Society , 2018
  4. Abstract:
  5. Conformational diseases, constituting a large number of diseases, have been connected with protein misfolding, leading to aggregation known as amyloid fibrils. Mainly due to the lack of detailed molecular mechanisms, there has not been an effective drug to combat amyloid-associated diseases. Recently, a small organic pyridazine-based molecule (RS-0406) has shown significant reductions in amyloid fibrils in both in vitro and in vivo animal studies. However, no information on molecular details of inhibition for the small molecule has been reported. In this work, we have decided to explore structure-activity relationship of pyridazine-based compounds to investigate structural parameters for amyloid inhibition. A number of closely related derivatives of RS-0406 were designed and synthesized to delineate the roles of structural properties, including bulkiness and halogen bonding, hydrogen-bonding ability, and the position of substituents on the flanking aromatic rings of the synthetic molecules. To examine the effectiveness of the synthesized compounds, amyloid fibril formation of hen egg white lysozyme was measured in the presence of each synthetic molecule. Our results indicated that in addition to the type of the aryl substituent, their positions on the ring were also important for their inhibitory roles in amyloid fibrils formation. Moreover, a fluorinated compound turned out to be a more effective kinetic inhibitor, displaying a delayed fibril nucleation than the original lead compound. Furthermore, biochemical structural analyses and molecular dynamics simulation revealed that the pyridazine-based compounds may mediate the inhibition of amyloid fibrils through stabilization of the protein monomer during partially unfolded state. The cytotoxicity assay revealed that the amounts of amyloid intermediates were reduced in the presence of the synthetic compounds. Eventually, IC50 values were obtained for the synthetic compounds, and quantitative structure-activity relationship method was employed to suggest more effective amyloid inhibitors. Copyright © 2018 American Chemical Society
  6. Keywords:
  7. amyloid ; hydrogen ; lysozyme ; n3,n6 di(3 chlorophenyl)pyridazine 3,6 diamine ; n3,n6 di(3 fluorophenyl)pyridazine 3,6 diamine ; n3,n6 di(3 hydroxyphenyl)pyridazine 3,6 diamine ; n3,n6 di(3 methoxyphenyl)pyridazine 3,6 diamine ; n3,n6 di(3 methylphenyl)pyridazine 3,6 diamine ; n3,n6 di(3 nitrophenyl)pyridazine 3,6 diamine ; n3,n6 di(3,4 dichlorophenyl)pyridazine 3,6 diamine ; n3,n6 di(4 bromophenyl)pyridazine 3,6 diamine ; n3,n6 di(4 chlorophenyl)pyridazine 3,6 diamine ; n3,n6 di(4 fluorophenyl)pyridazine 3,6 diamine ; n3,n6 di(4 hydroxyphenyl)pyridazine 3,6 diamine ; n3,n6 di(4 methylbenzoate)pyridazine 3,6 diamine ; n3,n6 di(4 nitrophenyl)pyridazine 3,6 diamine ; n3,n6 di(benzoic acid)pyridazine 3,6 diamine ; n3,n6 diphenylpyridazine 3,6 diamine ; Pyridazine derivative ; Unclassified drug ; Article ; Biological activity ; Controlled study ; Drug synthesis ; Hydrogen bond ; Inhibition kinetics ; Molecular dynamics ; PC12 cell line ; Structure activity relation
  8. Source: Chemical Research in Toxicology ; Volume 31, Issue 10 , 2018 , Pages 1092-1104 ; 0893228X (ISSN)
  9. URL: https://pubs.acs.org/doi/10.1021/acs.chemrestox.8b00210