Synthesis And Biological Activity Of Berberine Derivatives

In recent years, with the increase of cancer radiotherapy, chemotherapy, organtransplants, AIDS patients, and wide use of broad-spectrum antibiotics andimmunosuppressive agents, immunocompromised patients keep to increase, and thusresult in sharp rise in the incidence of deep fungal infections, fungal infections havebeen one of the leading cause of death for these patients. On the other hand, with thelong-term large-scale application of the antifungal agents, fungal resistance problemsbecome increasingly serious, and fungi can form various catheters mycelium orbiofilm in the human body or the surface of inert materials, to make it rightdrugsensitivity decreased by tens or even hundreds of times, that’s the main reason forclinical antifungal treatment failure.Berberine, as a natural isoquinoline alkaloid, mainly comes from plant Coptis asa quaternary ammonium ion of isoquinoline alkaloids, its rich in natural resources,mainly present in the Ranunculaceae Coptisthe Rutaceae Huang Bo, Berberidaceaeplant Berberis roots, while it was found in plants of Coptis, Papaveraceae,Menispermaceae, and Rhamnaceae. From the study results in recent years, it wasfound that berberine has a wide range of biological activity such as antibacterial,antiviral, anti-tumor, anti-arrhythmic, antimalarial, lowering blood sugar, loweringblood pressure, analgesic activity, becoming a research hotspot in recent years. In ourprevious study, we found that berberine can be used for collaborative azole antifungalagents against drug-resistant fungi.Like other isoquinoline alkaloids, there is a strong biological toxicity inberberine. Such as a large number of clinical appliaction of berberine, it will result inthe unpredictability of the sudden death phenomenon. Due to the chemical structure ofberberine showing a high degree of planar features, so that it is nither dissolved inwater nor in organic solvents, thus affecting the clinical appliaction of bioavailability.Although people have investigated berberine for mang years, but the above problemshaven’t been solved still. This study tried to solve the toxicity, poor solubility, poorbioavailability, and limited biological activity of berberine in clinical use as asynergist of antifungal agents in terms of reconstructure chemical structure.1. The reconstructure of berberine and structure-activity relationship researchThe reconstructure of berberine start from basis chemical structure of berberine,on one hand some chemical groups were added to berberine, on the other hand we removed some structure from the berberine. As a result, we have got five kinds ofnovel compounds (13-replaced Berberine derivatives, tetrahydroberberine derivatives,dihydroisoquinoline derivatives, tetrahydroisoquinoline derivatives, andphenylethylamine derivatives) which could be used to as a synergist of fluconazoleagainst clinical isolated resistant Candida albicans, and the structure-activityrelationship of berberine as a synergist of fluconazole against clinical isolatedresistant Candid albicans was summarized reasonably. On the other hand, by thetransformation of the structure of berberine, it’s planal charater of structure have beenbroken which caused the poor solubility. So we have found not only to maintain orenhance its biological activity, but also to improve its solubility compounds (such as3,4,5-compounds), provide a new direction to find antifungal synergist.2. Biological activity of berberine and its analoguesBiological activity of all kinds of berberine analogues were screened bysynergistic activity of fluconazolel e in resistant Candida albicans model, while goodin vitro biological activity of compounds were used to test in vivo activity by mousedeep fungal infection action model too. It can be seen from the biological tests: Thebioactivity and solubility of category5is better than berberine; Biological activityindex (MIC80value and FICI value) of compound category1,2,3,4,5and6showregular changes, and provide a basis for structure-activity relationship studies ofberberine as fluconazole anti-drug-resistant Candida albicans synergist.