Study On The Synthesis And Inhibition Of Tyrosinase Of Kojic Acid Derivatives Containing Phenol

Kojic acid derivatives are kinds of heterocyclic compounds contain pyrone structure. Many drug molecules with good biological activity contain pyrone structure. These compounds have a wide range of biological activities, such as anti-inflammatory, analgesic, anticancer, lowering blood sugar and inhibit tyrosinase activity. According to the drug design mosaic and active principle of superposition, a series of new kojic acid phenol derivatives were synthesized, then IR, MS, 1H NMR and 13C NMR were smployed to characterize the structure of derivatives, what’s more, we preliminarily discussed the structure-activity relationship, and evaluated the activity inhibition effect to tyrosinase. The main results are shown as Allows:1. We adopt improved method for the synthesis of intermediates 5-substituted-4-amino-3-thiol-1,2,4-triazole 1. These compounds were synthesized from carboxylic acid via activating carboxyl by using benzotriazole, hydrazinolysis, cyclization. The method compared with the conventional methods becomes more moderate and higher yield.2. With 4-amino of 5-substituted-3-thiol-4-amino-1,2,4-triazole nercaptan 1 proceeding condensation reaction with hydroxyl benzene formaldehyde,5-substituted-4-hydroxyl benzoate methylene amino-3-thiol-1,2,4-triazole 2 Schiff base was obtained, then with sodium borohydride to the reduction of C=N bond in Schiff base. What’s more, the reaction conditions were optimized and a better reaction condition was obtained. Among them, the optimal reaction conditions for the synthesis of Schiff base:ethanol as a solvent, hydroxybenzaldehyde and toluene sulfonic acid, the molar ratio is 1:1.2:0.2, the reaction temperature is 80℃, and reaction time is 4h; the best conditions for the reduction of the Schiff base: as the reaction solvent,5-substituted-4-hydroxy benzoate methylene amino-3-thiol-1,2,4-triazole Schiff base and NaBH4,the molar ratio i s 1:1.3, the reaction temperature i s 0℃,reaction time 6 min.3. Koj ic acid was reacted with thionyl chloride to get 5-hydfoxymethyl-chloro-4-pyrone 4,then under the action of a weak base triethylamine 5-substituted-4-hydroxy phenyl methyl amino-3-thiol-1,2,4-triazole 3, the de sired product kojic acid thioethers derivative s 5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methylthio]-4-hydroxy benzoyl amino-1,2,4-triazole 5 was obtained. What’s more, the reaction conditions were optimized to obtain optimum reaction conditions:DMF as solvent,the reaction temperature i s 80℃,and the feed ratio of 5-substituted-4-hydroxy benzoyl amino-3-thiol-1,2,4-triazole, 2-chl oro-5-hydroxy-1,4-pyrones and tri ethyl amine i s 1:1.2:1.2.4. The tyrosinase activity inhibition was studied with 9 target compounds,and preliminary result showed:all of these compounds can significantly inhibited tyrosinase, Among them, 5-phenyl-3-[5-hydroxy-4-pytone-2-yl-methylmercapto]-4-[2,4-Di hydroxy benzoyl amino-1,2,4-triazole on tyrosinase activity inhibition cffect is best,IC50 is 1.35μM...