Oxidative Heck Reaction as a Tool for Para-selective Olefination of Aniline: A DFT Supported Mechanism

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, IC values were obtained for the synthetic compounds, and quantitative structure-activity relationship method was employed to suggest more effective amyloid inhibitors.

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“…The IC 50 values were obtained from dose–response curves. In the second method, the IC 50 values were determined with QSAR method. , …”

Section: Materials and Methodsmentioning

confidence: 99%

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

Kalhor

Khodadadi

2018

Chem. Res. Toxicol.

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“…In 2017, Karimi and co-workers demonstrated the paraselective alkenylation of anilines under mild conditions using Pd(OAc) 2 and Cu(OAc) 2 (Scheme 31). 59 The presence of AcOH was crucial in maintaining the acidic conditions to diminish the strong binding of the nitrogen atom of aniline to the Pd(II) ion. Both terminal and internal alkenes were suitable for this transformation.…”

Section: Scheme 30 Aerobic Direct Olefination Of Anilines and Arenes mentioning

confidence: 99%

Recent Developments in Palladium-Catalysed Non-Directed C–H Bond Activation in Arenes

2019

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Over the past decades, organic chemists have focussed on developing new approaches to directed C–H functionalisations, where the site selectivity is steered by the presence of a directing group (DG). Nonetheless, in recent years, more and more non-directed strategies are being developed to circumvent the requisite directing group, making C–H functionalisations more generic. This short review focuses on the latest developments in palladium-catalysed non-directed C–H functionalisations of aromatic compounds.1 Introduction2 C–C Bond Formation2.1 C–H Arylation2.2 C–H Alkylation2.3 C–H Alkenylation2.4 C–H Carbonylation3 C–Heteroatom Bond Formation3.1 C–O Bond Formation3.2 C–N Bond Formation3.3 C–S Bond Formation4 Conclusion

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“…In 2009, Mao et al. reported samarium powder catalyzed Sonogashira reaction . The important features of Sm are being stable in air, cheap and easy to handle.…”

Section: Introductionmentioning

confidence: 99%

“…[26] In 2009, Mao et al reported samarium powder catalyzed Sonogashira reaction. [27] The important features of Sm are being stable in air, cheap and easy to handle. From the viewpoint of safety and economy and in continuation of our…”

Section: Introductionmentioning

confidence: 99%

A ligand and Palladium‐free Avenue for Cyanation of Aryl Halides: The Art of Samarium Powder in C–C Coupling Reaction

et al. 2019

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Oxidative Heck Reaction as a Tool for Para-selective Olefination of Aniline: A DFT Supported Mechanism

Cited by 26 publications

References 51 publications

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

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

Recent Developments in Palladium-Catalysed Non-Directed C–H Bond Activation in Arenes

A ligand and Palladium‐free Avenue for Cyanation of Aryl Halides: The Art of Samarium Powder in C–C Coupling Reaction

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