Synthesis And Biological Activity Of 5-Substituted-1-Azaanthraquinone Derivatives

Anthraquinone derivatives which were widely distributed in natural products and easy to get are good led compound in drugs’ discovery for their widely variety of pharmacological activities.However,these compounds containing bioactive constituents also suffered from frequent cardiotoxicity,low physiological activities and water insoluble that limited their applicability.Further structural modification appeared to be necessary for better promotion of the application of these compounds.A new series of 1-azaanthraquinone hybrids have been designed,synthesized and evaluated for their physiological activities such as anti-inflammatory,enzymes inhibition and antibacterial.The main works as shown as follows:Ten compounds 8a-8e and 9a-9e have been prepared by 1-azaanthraquinone.The differences of these compounds are substituents and length of linker on the 1-azaanthraquinone.These series of compounds have been designed and synthesized based on multi-target-directed strategy.Firstly,cell model of LPS-induced inflammation was established.Their accumulated amount of NO,TNF-α,IL-1β,IL-6 from RAW264.7 cell and their ability to inhibit these proinflammatory cytokines by Elisa were detected.Their expression quantity of iNOS in protein level by Western Blot was also tested.Secondly,the abilities of inhibiting cholinesterase(AChE),butyrylcholinesterase(BuChE)and Aβ1-42 of the synthetical derivatives were explored.Lastly,the minimum inhibitory concentration(MIC)of Micrococcus luteus,Staphylococcus aureus,Enterobacter aerogenes,Escherichia coli,Bacillus anthraci,Bacillus megaterium,Paratyphoidfever and Shigella was also assessed by double-dilution method doubling dilution.The result indicated that 5-substituted derivatives showed better IL-1β inhibitory and the minimum inhibitory concentration reached 1μM.With the concentration from 1μM to 10μM,the analogues have exhibited different inhibitory potency for NO、TNF-α and IL-6,especially,8b and 9b presentation a remarkably activity.Further,the two compounds 8b and 9b performed inhibitory potency for the expression quantity of iNOS in protein level,moreover,9b exhibited significant activity with 10μM from the Western Blot.Most of synthesized compounds presented marked AChE inhibitory potency with IC50 values from 1.08μM to 22,99μM,Derivatives 8a and 9a with IC50 values reached 1.08μM and 1.12μM respectively.In addition,the ten compounds showed moderate inhibitory potency toward Aβ1-42 aggregation.Antibacterial experiment showed that compounds 8a and 9a exhibited dramatically inhibitory ability in all tested analogues,especially for Staphylococcus aureus and superior to ampicillin sodium.Furthermore,the compound 8a with MIC value reached at 3.175μg/mL.