Synthesis and Structure Activity Relationship of Pyridazine-Based Inhibitors for Elucidating the Mechanism of Amyloid Inhibition

Chemical Research in Toxicology
Hamid R Kalhor, Alireza Nazari Khodadadi

Abstract

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...Continue Reading

References

Jan 31, 1995·Proceedings of the National Academy of Sciences of the United States of America·K C EvansP T Lansbury
Jul 12, 1997·Lancet·R W Carrell, D A Lomas
Dec 20, 2003·Nature·Christopher M Dobson
Jul 9, 2004·Journal of Molecular Biology·Erica FrareAngelo Fontana
Nov 24, 2005·The FEBS Journal·O Sumner Makin, Louise C Serpell
Jun 8, 2006·Annual Review of Biochemistry·Fabrizio Chiti, Christopher M Dobson
Jun 15, 2006·Quarterly Reviews of Biophysics·Robert Tycko
Mar 27, 2007·Biochemical and Biophysical Research Communications·Tomonori MishimaTadashi Ueda
Jun 26, 2007·Archives of Biochemistry and Biophysics·Yiwen ChenNikolay V Dokholyan
Nov 17, 2007·Cell Death and Differentiation·Craig C Mello
Feb 13, 2008·Archives of Neurology·Claudio Soto, Lisbell D Estrada
Apr 15, 2008·Quarterly Reviews of Biophysics·S Walter EnglanderMallela M G Krishna
Sep 4, 2008·IUBMB Life·Heath Ecroyd, John A Carver
Feb 1, 1948·Journal of the American Chemical Society·W C SCHNEIDER
Apr 2, 2009·Biochimica Et Biophysica Acta·Satish KumarRajaram Swaminathan
Jun 6, 2009·Nature Structural & Molecular Biology·F Ulrich Hartl, Manajit Hayer-Hartl
Feb 9, 2010·Behavioural Brain Research·Eugene O'HareEun-Mee Kim
Feb 13, 2010·The FEBS Journal·Mikael Lindgren, Per Hammarström
Sep 30, 2010·Journal of the American Chemical Society·Fanling MengAndisheh Abedini
May 21, 2011·Journal of Computational Chemistry·Mahmoud A A Ibrahim
Aug 19, 2011·Advances in Protein Chemistry and Structural Biology·Rajaram SwaminathanNividh Chandra
Jul 5, 2012·Cold Spring Harbor Perspectives in Medicine·Lennart Mucke, Dennis J Selkoe
Nov 14, 2012·The Journal of Physical Chemistry. B·Weixin XuYuguang Mu
Nov 14, 2012·Journal of Medicinal Chemistry·Rainer WilckenFrank M Boeckler
Jun 5, 2013·Organic & Biomolecular Chemistry·Weipeng LiHongxing Xin
Feb 25, 2014·Trends in Pharmacological Sciences·Paolo ArosioTuomas P J Knowles
May 24, 2014·Nature Reviews. Molecular Cell Biology·Tuomas P J KnowlesChristopher M Dobson
Jul 11, 2014·Scientific Reports·Hao GongKun Huang
Dec 1, 2015·Scientific Reports·Sinjan ChoudharyRamakrishna V Hosur
May 28, 2016·Scientific Reports·Parvez AlamRizwan Hasan Khan
Jun 30, 2016·Journal of the American Chemical Society·Michael T ColvinRobert G Griffin
Jul 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Marielle Aulikki WältiRoland Riek
Aug 30, 2016·Chemical Biology & Drug Design·Erika FerrariKatarina Siposova
Jan 11, 2017·Drug Research·Maiy Youssef JaballahKhaled Abouzid
Mar 14, 2017·Computational Biology and Chemistry·Ravichand Palakurti, Ramakrishna Vadrevu
Aug 5, 2017·The Journal of Physical Chemistry. B·Hamid R Kalhor, M Parsa Jabbari
Sep 7, 2017·The Journal of Organic Chemistry·Firouz Matloubi MoghaddamAshkan Karimi
Oct 17, 2017·Biomacromolecules·Emily H PilkingtonPu Chun Ke
Jan 9, 2018·MedChemComm·Renato Ferreira de Freitas, Matthieu Schapira

❮ Previous
Next ❯

Citations

Dec 6, 2020·International Journal of Biological Macromolecules·Hossein AshrafianRizwan Hasan Khan
Nov 14, 2019·Journal of Chemical Information and Modeling·Hamid R Kalhor, Mohammadparsa Jabbary

❮ Previous
Next ❯

Related Concepts

Related Feeds

Bacterial Cell Wall Structure (ASM)

Bacterial cell walls are made of peptidoglycan (also called murein), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids. Here is the latest research on bacterial cell wall structures.

Bacterial Cell Wall Structure

Bacterial cell walls are made of peptidoglycan (also called murein), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids. Here is the latest research on bacterial cell wall structures.