Study On The Antioxidant Properties Of Coumarin And Quinoline Derivatives

The investigation of biological antioxidants is one of the most important research topic in biochemistry, pharmaceutical chemistry and clinical medicine. In generally, antioxidants can be obtained by extracting from the nature or synthesizing in organic, in these two ways, organic chemistry plays an important role. It was found that the conjugated structure plays an important role in antioxidant activities, and the hydroxyl was a necessary functional group of antioxidants. Recently, the investigations of antioxidant focused on the structure modification of natural antioxidants, or introducing the traditional hydroxyl antioxidant functional groups to natural products structure skeleton. However, the studies on antioxidants with novel antioxidantive functional groups and constructing strutures containing two natural antioxidant skeletons were reported rarely. Therefore, in this work, a series of novel antioxidant owning two natural antioxidant skeletons or new antioxidantive functional groups have been synthesized via the modification of coumarin and quinoline structure derivatives, including coumarin-modified chalcones, coumarin-substituted dihydropyrazoles, coumestans, coumarin-fused coumarin, ferrocenylquinolines, ferrocenyl-substituted coumarin-fused quinolines, and imidazo[1,2-a]pyridines or quinolines. The radical-scavenging properties of the obtained compounds were estimated by quenching 2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical(ABTS+·), 2,2’-diphenyl-1-picrylhydrazyl(DPPH), and galvinoxyl radicals. The antioxidant effect has been evaluated by inhibiting the oxidation of DNA mediated by Cu2+/glutathione(GSH)-, hydroxyl radical(.OH)- and 2,2’-azobis(2-amidinopropane hydrochloride)(AAPH)-induced oxidation of DNA. The structure-activity relationship of these compounds have been explored, and the major work in this thesis is as the following:1. Study on the antioxidant properties of coumarin-modified chalcones and coumarin-substituted dihydropyrazoles.Seven coumarin-modified chalcones were synthesized by the modification of coumarin, firstly. Nine coumarin-substituted dihydropyrazoles were synthesized through the reaction between coumarin-modified chalcones and phenylhydrazine, subsequently. The substituent effect was researched in the above molecules. It was found that the hydroxyl was a necessary antioxidant functional group in coumarin-modified chalcones and coumarin- substituted dihydropyrazoles, and antioxidant effectiveness could be enhanced with the increasing of the hydroxyl number. In addition, coumarin-substituted dihydropyrazoles could protect DNA against AAPH-induced oxidation when a benzene ring was replaced by a ferrocene moiety. The antioxidant activities of coumarin-substituted dihydropyrazoles were better than coumarin-modified chalcones, indicating that spatial structure coumarin-substituted dihydropyrazole was better than plane configurations coumarin-modified chalcones on the effect of antioxidant activities.In summary, the hydroxyl and ferrocene group play an important role of antioxidant in the above structure. Meanwhile, the sterically effects can also enhance antioxidant effectiveness.2. Study on the antioxidant properties of coumestans and coumarin-fused coumarins.Seven coumestans and six coumarin-fused coumarins owning a large conjugated heterocycles structure were synthesized. It was found that coumestan structure skeleton without any substituent group can also inhibit AAPH,.OH, and Cu2+/GSH-induced oxidation of DNA, which was due to the molecular skeleton can quench radicals. The antioxidant effectiveness of coumestans can be enhanced whatever kind of substituent group was introduced. Hydroxyl is a necessary antioxidant functional group in coumarin-fused coumarins, which can inhibit multiple radicals-induced oxidation of DNA. Especially, it was found that-N(CH3)2 is a new helpful group to improve both of antioxidant activities of coumestans and coumarin-fused coumarins.In summary, the large conjugated heterocycles coumarin compounds showed an excellent antioxidant activity, leading to some functional groups without any antioxidant activity display a better effect on radical scavengers and protecting DNA.3. Study on the antioxidant properties of ferrocenylquinolines and ferrocenylsubstituted coumarin-fused quinolines.Twenty-two ferrocenylquinolines and fifteen ferrocenyl-substituted coumarin-fused quinolines were synthesized by Povarov three-component-reaction(3CR). It was found that ferrocenylquinolines and ferrocenyl-substituted coumarin-fused quinolines can inhibit AAPH-induced oxidation of DNA and quench radicals, owning to the introduction of ferrocene group. The antioxidant activities of the above structure compounds can be further improved by introducing the electron-donating group, especially,-N(CH3)2, ferrocene group and hydroxyl. Meanwhile, antioxidant activity had a positive correlation on the quantity of these groups. In addition, the introduction of hydroxyl group cause the coumarin-fused quinolines can also quench DPPH and galvinoxyl radicals. Moreover, the antioxidant activity of ferrocenyl-substituted coumarin-fused quinolines was better than ferrocenylquinolines, indicating that the extention of conjugated system can improve the antioxidant activities of these compounds.In summary, ferrocene group can make quinolines and coumarin-fused quinolines emerge excellent antioxidant activity in inhibiting radicals induced oxidation of DNA. Meanwhile, both by introducing electron-donating group and increasing conjugated system are effective strategy on improving the antioxidant activities of the ferrocenylquinolines and ferrocenyl-substituted coumarin-fused quinolines.4. Study on the antioxidant properties of imidazo[1,2-a]pyridines or quinolines.Sixteen imidazo[1,2-a]pyridines or quinolines with different substituent were synthesized by using Groebke three-component-reaction(3CR). It was found that both imidazo[1,2-a]pyridines and quinolines derivatives can inhibit AAPH-induced oxidation of DNA and quench radicals, indicating the N-atom of fused heterocycles can quench radicals, in turn to inhibit AAPH-induced oxidation of DNA. The antioxidant activity of the nitrogen atoms in above structure can be further enhanced by introducing hydroxyl or ferrocene group, and the antioxidant activity had a positive correlation on the quantity of substituent. Meanwhile, increase conjugated system can also improve the antioxidant activities of the above compounds. Only hydroxyl-substituted imidazo[1,2-a] pyridines can quench galvinoxyl radicals, indicating the N-atom of fused heterocycles and ferrocene group were invalid to oxygen-center free radical. Introducing ferrocene group and increasing conjugated system can reduce the oxidative potential(E1/2) of these compounds, and improve the complexation with DNA, and thus increase their antioxidant activity.In summary, the N-atom of fused heterocycles synthesized via Groebke-3CR revealed excellent antioxidant activity. Both by introducing the ferrocene group and increasing conjugated system can improve the effect on quenching galvinoxyl radicals of imidazo[1,2-a]pyridines or quinolines derivatives.In this thesis, the modification and transformation of coumarins and quinolines is a successful and effective method to construct the novel antioxidants, even some structure skeleton without any substituent can also show antioxidant activity, meanwhile, ferrocene group and-N(CH3)2 reveal the same effect as hydroxyl group on increasing the antioxidant activity of these structure.