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