Design, Synthesis And Antibacterial Mechanism Of Novel Pleuromutilin Derivatives Containing A Phenyl Piperzanie Ring

Pleuromutilin was first isolated from by Pleurotus multilus(Fr.) Sacc. And Pleurotus Passecke-rianus Pilat by Kavanagh in 1951. Pleuromutilin and its derivatives had strong antibacterial abilities against Staphylococcus aureus and Mycoplasma.In order to obtain novel pleuromutilin derivatives with better antibacterial abilities,17 pleuromutilin derivatives containing phenyl-piperzanie were designed and synthesized. Pleuromutilin was used as starting material, the hydroxy of C14 branch chain was modified to tosyl, intermediate product with activated C14 branch chain was acquired. The intermediate product reacted with Na I to make it more active, then reacted with a series phenyl-piperzanie and gave the crude product.All of these compounds were purified via column chromatography, verified chemical structure via infrared spectrum and nuclear magnetic resonance(1HNMR and 13CNMR), the structure of 17 product were consistent with design structure. Minimal inhibitory concentration of these ompounds against S..aureus(ATCC29213), S.aureus isolated from Guangdong area(Sa1) and E.coli.(ATCC25922) were tested using agar dilution method, the result showed compounds with mete-position substituent group or strong electron withdrawing group had better antibacterial activities. 26 b, 28 b and 29 a had better activities than Tiamulin, 29 a, containing an ortho-position nitryl, had the best activities among these derivatives.26b, 28 b and 29 a were chosen to execute molecular docking with the 50 S ribosome subunit crystal structure(PDB ID:1XBP). The binding free energy of 26 b was-12.99 kcal/mol, and it had a hydrogen bond wih G2484, 28b’s binding free energy was-12.12 kcal/mol, it interacted with G2044 and G2484 by two hydrogen bond. 9 residues around binding site away from 29 a less than 3?, the conformation of 29 a was similar with hole around by residues.Minimal inhibitory concentration and molecular docking show the antibacterial mechanism of these series derivatives, three compound exhibited good antibacterial activities.