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A facile tandem double-dehydrative-double-Heck olefination strategy for pot-economic synthesis of (E)-distyrylbenzenes as multi-target-directed ligands against Alzheimer's disease employing C. elegans model

Andhare, Nitin H., Thopate, Yogesh, Shamsuzzama,, Kumar, Lalit, Sharma, Tanuj, Siddiqi, M.I., Sinha, Arun K., Nazir, Aamir
Tetrahedron 2018 v.74 pp. 1655-1667
Alzheimer disease, Caenorhabditis elegans, acetylcholinesterase, amyloid, benzene, bromine, catalysts, chemical structure, enzyme inhibition, genetically modified organisms, hydroxylation, ionic liquids, ligands, lipids, molecular models, palladium, polymerization, reactive oxygen species, receptors, regioselectivity
A concise, one pot and regioselective access to (E)-distyrylbenzenes (DSBs) from arylhalide and secondary phenylenediethanol, a stable precursor for in situ generation of divinylbenzene (DVB) to avoid its polymerization, is described for construction of double CC bond formation via tandem double-dehydrative-double-Heck (D-D-D-H) reaction using Palladium and ionic liquid [hmim]Br as a cooperative catalyst. It is noteworthy that this pot-economy approach also provides direct synthesis of hydroxylated distyrylbenzenes without requirement of protection-deprotection strategy. Importantly, the synthesized DSBs are tested for their protective activity against β amyloid reduction, acetylcholine esterase inhibition, lipid lowering and reactive oxygen species (ROS) reduction properties in transgenic Caenorhabditis elegans model wherein 1,3-bis((E)-4-(trifluoromethyl)styryl)benzene (5c) is found to be active across all above factors thus presenting lead molecule within multi-target-directed ligands (MTDLs) approach. Molecular docking studies were also performed to understand the interactions of potent DSBs with receptors.