Research On The Biological Activities Of Paeonol, Paeonol Derivatives And Structural Analogues

Paeonol (2-hydroxy-4-methoxy acetophenone) is one of the main activeingredients of traditional Chinese medicine from the root barks of Paeonia Suffruticeosa Andr and the dried root and the entire plants of Pyenostelma Panicu latum(Bunge) K Schum, with a wide range of biological activities, such as anti-bacterialanti-inflammatory, analgesic, antipyretic, sedative, hypnotic, anti-tumor, anti-allergicand prevention of cardiovascular system diseases. In this study the methods ofextraction and synthesis of paeonol were optimized and the derivatives and structuralanalogues of paeonol were synthesized by modification and transformation of themain functional groups. The biological activities (antioxidant, antibacterial andantiviral activity) of Paeonol of paeonol derivatives and structural analogues werestudied comparatively to seek the relationship between structure and activities.Results are as follows:1.2,4–Dihydroxyacetophenone, paeonol and its four structural analogues wereprepared by chemical synthesis,10derivatives and structural analogues weresynthesized with the structure of the paeonol and2,4-dihydroxyphenyl ethanone astemplates including methylated product, the esterification product, phenoxy aceticacid derivatives, allyl-etherified products and the Claisen rearrangement product, thereaction product with richloroacetic acid, halogenated product on the side chain ofpaeonol and the reduction product of the carbonyl group. Among them there are fourkinds of compound (4-methoxy-2-allyloxy-acetophenone,3-allyl-2-hydroxy-4-methoxy-acetophenone,2-hydroxy-4-allyloxyacetophenone and5-allyl-2,4-dihydroxyphenyl ethyl ketone) were first synthesized.2. The antioxidant activity (scavenging of hydroxyl radical (OH), superoxideanion radical (O2-), scavenging DPPH, scavenging capacity of mouse liver tissuelipid peroxidation) of16compounds including paeonol, derivatives and structuralanalogues of paeonol were tested. The conclusions were obtained as follows bycomparing the different structures of the compounds and the difference scavenging abilities on the free radicals:(1) The participation of the four anti-oxidation reactions of the above-mentioned16kinds of compounds had close relationship with the number of phenolic hydroxylgroup, which showed that the phenolic hydroxyl group is the necessary functionalgroup among these kinds of molecules having anti-oxidation activites. Theintroduction of an allyl group on the benzene rings in the molecule can play the roleof enhanced activity.(2) An acetyl group also played an important role in the reaction, but it is notnecessary for the functional group. The presence of an acetyl group on the benzenering significantly reduced the activity of clearing OH, but significantly enhanced theactivity of scavenging O2-radical.(3) Five compounds with a wide range of strong antioxidant activities were confirmedby screening, including No.16(5-allyl-2,4-di-hydroxyacetophenone), No.10(3-allyl-2-hydroxy-4-methoxy compoundsacetophenone), No.1(2,4-di-hydroxyacetophenone), No.3(2,5-di-hydroxyacetophenone) and No.14(2-ethyl-5-methoxy-phenol).3. The antibacterial activities on four kinds of bacteria and10kinds ofpathogenic fungi of16compounds including paeonol, derivatives and structuralanalogues of paeonol were tested, with resorcinol (the synthesis starting compounds)as the control samples. The conclusions were obtained as follows by comparing thedifferent structures of the compounds and the difference antibacterial activities on thebacteria and pathogenic fungi.There are11kinds of compounds having higher inhibition activities on bacterialand fungi, wherein No.10and No.16had especially significant activities. With thepresence of them at the concentration of0.5g/L, the above-mentioned four kinds ofbacteria, and10kinds of pathogenic fungi growed almost impossiblely.There are similarities and differences of the functional group to inhibit bacteriaand to inhibit the fungi. Similarities: Acetyl group in the molecules played a veryimportant role in the inhibitory effects, which can greatly enhance the antibacterialactivity; The allyl group introduced on the benzene ring can greatly enhance the corresponding inhibitory capacity, the5position is better than the3position as it isintroduced. When4-OH was changed to methoxy, allyloxy, ethoxy, the antibacterialactivities were not changed greatly. Differences: when the2-OH was changed toallyloxy group and an acetyl group, the antibacterial activities had a slight decrease,but antifungal activities were significantly reduced, even disappeared at the sameconcentration.4. The16compounds of paeonol, paeonol derivatives and structural analogueswere tested as materials, the heart leaf tobacco which were easily infected with thetobacco mosaic virus tobacco varieties were studied as the research object; weobtained the structure with highly anti-viral activity by initial screening. Through theanalysis of the structure-activity relationship, the conclusions can be speculated asfollows:(1) The most important factor which affect the antiviral activities of such compoundswas the number of phenolic hydroxyl groups in the molecule, with the more numberof phenolic hydroxyl group leading to lower antiviral activities.(2) When2-phenolic hydroxyl group was changed into acetate, the resistance activityof compounds to TMV virus will be greatly enhanced.(3) When the2-hydroxyl group of the phenol was changed into allyloxy-acetoxy, theanti-TMV virus activity of the compound will be improved, but the effect was lessthan that of acetate significantly. When the acetyl group in the molecule occurs as theα-bromo or the4-methoxy occurs as4-ethoxy, the anti-TMV virus activity did notchange significantly, which indicatied that these were not the important factors toaffect the anti-TMV virus activity.In summary, if the compounds having higher antioxidant activities, antibacterialactivities and antiviral activities were designed and synthesized in the subsequentstudy, the introduction of active functional group, the modification and transformationof the molecular structure can be obtained according to the above conclusions.