Design, Synthesis And Biological Evaluation Of Flavonoid Derivatives As Cardiovascular Agents

Flavonoids are natural compounds bearing a C₆-C₃-C₆ skeleton with diverse pharmacological properties.Due to their low toxicity,the chemopreventive effects of flavonoids on chronic diseases(e.g.cardiovascular diseases) have been paid much attention.The epidemiological studies demonstrated that people can lower incidence of heart diseases if they have a high dietary intake of flavonoids.Flavonoids have been found to possess antiatherogenic and antiaggregant effects and vasodilatory effects in isolated vascular preparation and animal models.However,there are some drawbacks of flavonoids limited their further application,such as low bioavailability and not enough potent activities.Previously,it was found that the vasorelaxant activities of flavonoids had positive correlation with their Log P values.Herein,we described the synthesis of twenty eight lipophilic flavonoid derivatives and investigated more systematically about the correlation between their CLogP and vasorelaxant activities through introduction of allyl,reduction of hydroxyl group or aleration of the skeleton.According to the results of above work and the vasodilator or nonvasodilator in other reference,2D-QSAR and 3D-QSAR models were established by SVM and CoMFA,respectively.Successively, twenty eight prenylflavonoids with promising activities were selected and synthesized. Among them,most compounds showed potent vasorelaxant activies.The theoretical results of them were consistent with their experimental values.Further vasorelaxant mechanism and vascular protective studies indicated that 1-16g,one of the most potent compounds,mainly exhibited endothelium-dependent vasorelaxant activities and could remarkable protect the vascular endothelium against oxidative stress.In addition,the neuroprotective effects of twelve prenylflavonoids were evaluated and most of the tested compounds could significantly inhibit the PC12 cell injury induced by OGD.The above studies could provide the basis of development novel cardiovascular agents.With the aim to develop hybrid cardiovascular agents,the scaffold hoping and molecular hybrid strategies were applied.Eleven hybrid compounds including chalcone derivatives bearing different NO donor(including Nitrate and Furaxan),and 4-phenyl-1,4-dihydropyridines derivatives bearing different chalcones were synthesized. Gratifyingly,most compounds showed good vasorelaxant activities and are much more potent than the chalcones.The compound 1-32c is the most potent one(EC₅₀=2.9μM, E_max=104.0%).According to that CysLTs result in atherosclerosis and other cardiovascular diseases and CysLT antagonists showed potential value for treatment of cardiovascular diseases.A novel pharmacophore model(Hypol) of CysLT₁ antagonists was constructed by Catalyst/HypoGen and used to "In Silico" evaluated the novel designed carboxyl chalcone derivatives.Then,eighteen compounds were selected and synthesized.Some of them showed potent CysLT₁ antagonistic activities.Furthermore, the 3D structure of CysLT₁ was firstly constructed by homology modelling.Molecular docking studies indicated that 2-39k could bind very well to CysLT₁ through hydrophobic,hydrogen bond and Electrostatic interaction.The results provide important structural information of CysLT₁ and its antagonist for further design of novel and more potent CysLT₁ antagonists.In addition,we have developed an efficient and rapid microwave-assisted synthesis of a range of Mannich base derivatives of 2-hydroxychalcones,as well as a facile method of one-pot synthesis of 3-benzyl-flavone derivatives.The distinct features of these two methodology included simple procedure,easy purification and good yields.The methods provided a rapid and efficient approach for preparation of these two series of compounds.