Design,Synthesis Of Fusidic Acid And Pentacyclic Triterpenoids Derivatives As Potential Antibacterial And Anti- Inflammatory Agents

Antibacterial drugs can effectively prevent and treat bacterial infections, and the role it plays in daily life has become more and more significant. However, the unreasonable use of antimicrobial drugs causes the appearance of the resistant bacterial strains. Terefore, a reasonable and effective control of the hazards caued by bacterial infection becomes much more urgent.Fusidic acid, as a natural antibacterial drug, has been widely applied to the clinical prevention and treatment of bacterial infections, especially the infections caused by staphylococcus aureus. Nonetheless,due to its narrow antimicrobial spectrum and some side effects the clinical application of it has been limited. Pentacyclic triterpenoids, one kind of the natural small molecule with special structure, has received extensive attention in the aspects such as the anti cancer, anti diabetes, etc, whereas few study has been applied to its antibacterial aspect.Fusidic acid and pentacyclic triterpenoids (ursolic acid, oleanolic acid and glycyrrhetinic acid) were chosen as parent compounds to modify adopts the chemical modification methods including esterification, oxidation, substitution, condensation, etc to transform their structures.In this study, 130 derivatives were obtained among which 100 new compounds were first reported. In addition, all of the derivatives’ structure were characterized and the size of the bacterial inhibition zone and the minimum inhibitory concentration were also studied in this research. Furthermore, the anti-inflammatory activity of fusidic acid and its hydrogenation derivative was also investigated.C-3, C-24 to C-25 positions of fusidic acid were chosen as the modification positions, 52 derivatives were obtained. And the antibacterial activity and structure-activity relationship studies implied that while the ester group in C-3 position linked with a cyclic group showed better antibacterial activity. Their activities were similar with the parent compound fusidic acid (MIC = 0.2～6 μM). While the C-3 position was replaced with other atom or group, such as halogen, azide, amine, etc. It still showed obvious bacteriostatic activity while it was lower than fusidic acid, which will be used for further structural optimization.Three kinds of pentacyclic triterpenes were selected in this study. Jones oxidation and Claisen Schmidt Condensation were introduced to modify these three compounds. 79 derivatives were obtained, including 33 UA derivatives, 24 OA derivatives and 22 GA derivatives. Both OA and UA derivatives showed no antibacterial activity which MIC higher than 200 μM. However, GA derivatives showed a potential antibacterial activity which is potential than GA. These derivatives showed higher activity (MIC=3-25 μM) to sensitive bacterial strains than MRSA (MIC=12～100 μM). It has better activity while the structure has halogen atom or halogen-containing group, which may according to the carboxyl and carbonyl group in the structure of glycyrrhetinic acid.Both fusidic acid and its hydrogenation derivative have similar antibacterial activity. It may have different kinds of inflammatory response when the body was infected. Therefore,the anti-inflammatory activity of fusidic acid and its hydrogenation derivative were evaluated and the mechanism was also explored in this study. The result showed that both the two compounds can effectively inhibit the mice ear edema. The effect of WU-FA-2H was similar with the positive control while at the concentration of 8 μpg/μL. Furthermore, both of them also can reduce keratinization and inflammatory cells proliferation in this model, especially compound WU-FA-2H.More importantly, this dissertation also provides a preliminary exploration to the possible mechanism of anti-inflammatory action. Because TPA is the inducing factor of NF-κB signal pathway which can induce the production of the pro-inflammatory factors such as TNF-α,IL-1β, COX-2 and so on. The experimental results showed that the fusidic acid, especally the hydrogen fusidic acid, can effectively inhibit the production of the relevant pro-inflammatory factors, and it changes in a dose-dependent manner with the changing of drug concentration.The reason for this process might be the activation of the impact factor IKK in the upstream of IκBα is restrained and thus the production of inflammatory factors like TNF-a, IL-1β and COX-2 were inhibited and the production of p65 as well as the phosphorylation of IκBα is also reduced. In this way, it appears certain anti-inflammatory activity and lays a foundation for the new use of fusidic acid and its derivatives.