Studies On Synthesis And Antimicrobial Activity Of9-O-substituted Palmatine Analogues

Palmatine, a member of quaternary protoberberine alkaloid, which was extractedfrom common fibraurea stem that is a traditional Chinese medicinal plant, has a widevariety of biological activities，such as antimicrobial, antiviral, antitumor, hypotensive,protection of myocardial infarction, enhancing the immune, hypoglycemic, antioxidant,antiarrhythmic, sedation and liver activities, etc. Palmatine has been used to treat variousinflammatory diseases, such as bacillary dysentery, enteritis, surgical infection, gynecologicalinflammation, pink eye, respiratory tract and urinary tract infection, etc. Palmatine is a naturalantimicrobial and anti-infective drugs, but because of its fat-soluble poor and low of oralbioavailability, largely limiting its clinical application. Hence, we need to increase itsfat-soluble for improving its bioavailability by appropriate structural modification ofpalmatine.In the work described here, we designed and synthesized two series of eleven newcompounds by introducing different length alkyl or alkyl with N-heterocyclic structures atC-9-O of leading compounds palmatine. These compounds were characterized by1H NMR,13C NMR and ESI-MS.The antimicrobial activities of9-O-alkylpalmatine analogues3a-3f were investigated bypaper disc method and2-fold serial dilution test. The results showed that antibacterialactivities of compounds3a-3f were much higher than palmatine, especially againstGram-positive bacteria. The compounds9-O-butylpalmatine3d have higher antimicrobialactivity. The structure-activity relationships of compounds3a-3f were discussed.According to the literature and test summary, defining five factors and four levels, thesynthesis condition of9-O-butylpalmatine3d was optimized by L16(45) orthogonal table. Wedetermined the optimal reaction conditions. And we found that bromobutane dosage, theamount of potassium carbonate and the reaction time had a significant impact on the reaction,which for synthesis conditions of compound3d are optimized to provide a more precisedirection.Esomeprazole was invented as a proton-pump inhibitor for the inhibition of gastric acid secretion to be used in patients with peptic ulcers. We designed and synthesized two(D)-(-)-tartaric acid diamide chiral ligands6a and6b, which were characterized by1H NMR.In addition, according to the literature, omeprazole sulfide7was synthesized for synthesis ofesomeprazole through asymmetric oxidation. Single factor tests were conducted to find theoptimal reaction conditions of asymmetric oxidation synthesis of esomeprazole by chiralligand6a and Ti(O-iPr)4complex as catalyst, CHP as oxidant. Under the optimized conditions,we found that6b and Ti(O-iPr)4complex as catalyst showed much higher catalytic activityand enantioselectivity.