Synthesis And Biological Activities Of Novel Matrine And Triazoles Derivatives

Cirrhosis is recognized as one of the serious disease which a threat to the health ofhuman, liver cancer can be led by advanced cirrhosis. Liver fibrosis is considered to be anecessary link in the development from kinds of liver disease to cirrhosis.Liver fibrosis isthe pathologic process of intrahepatic paraplasm caused by kinds of virulencefactors,resulting in intrahepatic diffusivity excessive deposition of extracellular matrix.It isthe necessary link of chronic liver disease to cirrhosis.Matrine is a alkaloid extracted from Sophora.Sophora has been known for its effect ofliver protection and cholagogue.Matrine,one of its active ingredients, can be used forantifibrotic.M19is discovered as a highly reactive thio matrine derivatives by our group inrecent years, with significant hepatic fibrosis. Aqueous solution of the compound is good,but less stable, easily decomposed become sophocarpine thiosulfate in aqueous solution.With M19as the lead compound of the topics, larger aliphatic amines and aromaticamines were introduced to improve the stability and lipid-water partition of the compound.In this study, seven compounds were designed and synthesised.All the compounds werefirst reported. The structures of these compounds were confirmed through NMR and MS.The proliferation inhibitory activities of target compounds towards LX-2and T6weremeasured by MTT. Preliminary pharmacological results of the tests showed that most ofthe compounds which were synthesized by this subject had strong inhibitory activitiestowards two hepatoma cell lines.Compounds1e and1f exhibited better activity than M19. Currently, a multiple trend of fungal infection is being shown in clinic, which Candidaalbicans, Cryptococcus neoformans and Aspergillus fumigatus infections increaseddramatically, fungal disease has become a serious threat to the humans health as a majorkiller. Azole drugs are most widely used in the clinical, FCZ and ICZ as the representativesof the drug because of its good effects, side effects, broad spectrum antimicrobialcharacteristics has become a first-line treatment medicine of fungal infections in clinical.However, with its widespread application, its resistance has become a major barrier to limitits application. Other antifungal agents used clinically earlier such as amphotericin B, because of its toxic side effects;5-fluorouracil because of its recurrence there are manydeficiencies. Therefore, the development of high efficiency, low toxicity, broad-spectrumantifungal increasingly attracted attention domestic and abroad. Based on thecharacteristics of FCZ and ICZ, triazole antifungal drug is still one of the hotspots in thedevelopment of new antifungal drugs.According to QSAR and mechanism action of azole antifungal drugs, keep aneffective2,4-difluorophenyl, tertiary alcohols triazole ring structure fragments in theintroduction of hydrophobic side chains dithiocarbamate (Dithiocarbamates, DTCs)structure, it is envisaged by the introduction of a hydrophobic side chain is preferably athioester, a hydrophobic cavity in the role of the cytochrome P450enzyme active site.Better to look for the activity of triazole compounds.By ring-opening reaction, esterification and nucleophilic substitution reactions threecategories of57target compounds were designed and synthesized. The innovation of thistopic is to introduce the method and structure of thin DTCs fragment columnchromatographic purification of target compounds. After searching, all the compoundswere first reported and their compound structure were confirmed by NMR and MS.MICs of all title compounds were determined by the method recommended by theNational Committee for Clinical Laboratory Standards (NCCLS) using RPMI1640testmedium. The MIC80values showed most compounds exhibited activity against mostfungies. Some compounds exhibited better activity against Candida albicans (ATCC14053)、SCZ20352and Candida parapsilosis (90018) than FCZ, most close to or better than5-F.Allthe compounds exhibited strong activity against Candida Albicans,most compoundsexhibited activity against FCZ. Compounds2a-2f and2k have a broad-spectrum antifungalactivity. Some of the title compounds are worthy of further pharmacological study.