Design Synthesis And B Iological Activity Of Pleuromutilin Derivatives

Antibiotics are a class of secondary metabolites with anti-pathogen or other biological activity, it produced by microorganisms(including bacteria, fungi and actinomyces) or higher plants and animals in the process of life, and can interfere with normal growth and development of other cells. Antibiotics have good inhibitory and killing effect on pathogenic microbes, such as bacteria, fungi, mycoplasma, chlamydia, spirochetes and so on, but ineffective against viruses, such as influenza virus. While they have certain side effects on humans and animals, even at therapeutic doses. Since penicillin used for clinically in 1943, there are several thousands of types of antibiotics have been found, and hundreds of them have been applied in clinical. The main sources of antibiotics are microorganism culture liquid extraction and semi-synthetic.Pleuromutilin is a compound having antibacterial activity reported in 1951 by Kavanagh. It was separated from Pleurotus passeckerianus and is composed of 5-6-8 tricyclic diterpene. It can inhibit the growth of Gram-positive bacteria and mycoplasma. By studying the crystal structures of deinococcus radiodurans ribosomal subunit with different pleuromutilin derivatives, we found all the mother nucleus of pleuromutilin are combined with the A site of PTC and their C14 side chain are extended to the P site of ribosome peptidyl transfer center. The side chain can inhibit e the activity of the peptidyl transferase by preventing the bind of aminoacyl t RNA with the P site and then prevent bacterial protein synthesis to inhitite the growth of bacterials. Pleuromutilin and its derivatives only inhibit the protein synthesis of prokaryotic cells, no effect on eukaryocyte and mammalian ribosomes. They hardly have cross-resistance with other antibiotics.In this thesis, we first studied and summarized the quantitative structure-activity relationship(QSAR), mechanism and research progress of pleuromutilin der ivatives. And based on the former work, we designed and synthesized of three categories, a total of 44 novel pleuromutilin derivatives. Piperazine ring was used as spacer in the first kind of derivatives and alkylamine and arylamine as hydrophilic and hydrogen bond donors in the end of the side chain, a total of 19 compounds were synthesized. Piperazine ring was also used as spacer in the second kind of derivatives and based on the twin drug principles, we chose p-amino benzenesulfonyl as the terminal active group, a total of 9 compounds were synthesized. Some articles reported that the sulfide linkage derivatives show potent in vitro antibacterial activity. So we designed and synthesized a series of compound which containing sulfide linkage, p-aminothiophenol was chosen for linkage group and p-amino benzenesulfonyl was also chosen for terminal active group, a total of 16 derivatives were synthesized. The aforementioned 44 compounds were purified by recrystallization and chromatography column method. All the structures of pure derivatives were confirmed by IR, 1H NMR, 13 C NMR and MS.In this paper, we tested the in vitro activity of the 44 Pleuromutilin derivatives on six Gram-positive bacteria, the minimum inhibitory concentration(MIC) data show that four compounds exhibit equal activity compared with tiamulin, 13 compounds were better than the control drugs, and five compounds exhibit effect on resistant Staphylococcus aureus.By means of computer-aided drug design(CADD), derivatives 5b, 5d, 10 b, 10 d, 15 e, 15 f, 17, 20 a, 20 e, 22 a and 22 b were operated to molecular docking studies, Describes the binding mode of these derivatives with of the active site, and provide reference and gist for the design of derivatives in subsequent.