Study On The Synthesis And Biological Activity Of Kojic Acid Derivatives Containing1,2,4-triazole

Kojic acid derivatives are kinds of heterocyclic compounds contain pyrone structure.Many drug molecules with good biological activity contain pyrone structure. Thesecompounds have a wide range of biological activities, such as anti-inflammatory, analgesic,anticancer, lowering blood sugar and inhibit tyrosinase activity. According to the drug designmosaic and active principle of superposition, in order to improve its stablitity and biologicalactivity,11compounds5-substituted-4-[5-hydroxy-4-pyrone-2-yl-methylene amino]-3-thiol-1,2,4-triazole34and4compounds5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methyllmercapto]-4-amino-1,2,4-triazole35were synthesized from kojic acid. Their structures werecharacterized by IR, MS,1H NMR and13C NMR. The main results are shown as fowllows:1. We adopt improved method for the synthesis of intermediates5-substituted-3-thiol-4-amino-1,2,4-triazole40. These compounds were synthesized from carboxylic acid viaactivating carboxyl by using benzotriazole, hydrazinolysis, cyclization. The method comparedwith the conventional methods becomes more moderate and higher yield.2.5-(4-methoxy-benzyloxy)-2-hydroxymethyl-4-pyrone41was synthesized by reactionof kojic acid with methoxybenzyl chloride. Then, DMP reacts with5-(4-methoxy-benzyloxy)-2-hydroxymethyl-4-pyrone41directly and compound5-(4-methoxy-benzyloxy)-2-formyl-4-pyrone42was obtained. Then,5-hydroxy-2-formyl-4-pyrone43was synthesized from5-(4-methoxy-benzyloxy)-2-formyl-4-pyrone42via deprotection. At last, under the aciditycondition,5-substituted-4-[5-hydroxy-4-pyrone-2-yl-methyleneamino]-3-thiol-1,2,4-triazole34were synthesized by5-(4-methoxy-benzyloxy)-2-formyl-4-pyrone42reacts with5-substituted-3-thiol-4-amino-1,2,4-triazole40. The optimal synthesis conditions of productswere obtained. such as: the molar ratio of5-(4-methoxy-benzyloxy)-2-fomryl-4-pyrone and5-substituted-3-thiol-4-amino-1,2,4-triazole was1:1.20, the amount of concentratedhydrochloric acid was1ml, the reaction time was6h.3.5-hydroxy-2-chloromethyl-4-pyrone44was synthesized by reaction of kojic acid withthionyl chloride. Then under the weak base condition,5-hydroxy-2-chloromethyl-4-pyrone44reacts with5-substituted-3-thiol-4-amino-1,2,4-triazole40and target compounds5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methylmercapto]-4-amino-1,2,4-triazole35were obtained. The optimal synthesis conditions of products were obtained such as: the molar ratioof5-substituted-3-thiol-4-amino-1,2,4-triazole and5-hydroxy-2-chloromethyl-pyran-4-onewas1:1.2, the reaction temperature was80℃, the reaction solvent was DMF.4. The target compounds were screened for their anti-trosinase activity. Preliminaryresults showed that the majority compounds have obvious inhibitory effect on tyrosinaseactivity, and5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methylmercapto]-4-amino-1,2,4-triazole35are more pronounced than the effect of5-substituted-4-[5-hydroxy-4-pyrone-2-yl-methylene amino]-3-thiol-1,2,4-triazole34, Among them,5-phenyl-3-[5-hydroxy-4-pyrone-2-yl-methylmercapto]-4-amino-1,2,4-triazole on tyrosinase activity inhibition cffect is best,and its IC50is5.82μM.