Water Solubility Improvement And Biological Activity Of Study The New Pleuromutilin Derivatives Possessing 2-Aminobenzenethiol Linker

The pleuromutilin has obvious antibacterial activity and good pharmacokinetic properties on resistant gram-positive bacteria and mycoplasma,but its water solubility is poor.By modifying the side chain of pleuromutilin C14,replacing the terminal hydroxyl group with a thiol compound to form a thioether acetyl side chain derivative.Studies have shown that most thioether acetyl side chain derivatives can increase their antibacterial activity by directly accessing a thiol-containing reactive group.Thus developed antibacterial activity,water solubility is significantly better than pleuromutilin tiamulin,Wooni Miao Lin and so on.The pleuromutilin derivatives containing a 2-aminobenzenethiol side chain with a thioether acetylene side chain and serving as a linker have strong antibacterial activity but poor water solubility.Most of the compounds with piperazine ring have good pharmacokinetic properties and can increase the water solubility and metabolic stability of the compound.The introduction of pleuromutilin derivatives containing a secondary amine structural skeleton into the C-14 side chain enhances its antibacterial activity.This article mainly chemically modified the terminal amino group of the pleuromutilin derivative containing a 2-aminobenzenethiol side chain.Piperazine ring and secondary amine were introduced,and 25 kinds of pleuromutilin derivatives were designed and synthesized.The constituents were isolated and purified by silica gel column chromatography and confirmed by high resolution mass spectrometry?HRMS?,nuclear magnetic resonance?¹HNMR?and carbon(¹³C NMR)spectra and infrared?IR?.The 25 structures were not reported.To study the in vitro antibacterial activity of the 25 derivatives obtained against S.aureus ATCC29213,Methicillin-resistant Staphylococcus aureus?MRSA?ATCC43300,and clinical isolate AD3.The minimum inhibitory concentrations of 25 derivatives against Staphylococcus aureus ATCC29213,Methicillin-resistant Staphylococcus aureus ATCC43300,and clinical isolate AD3 were 0.03 to 8?g/ml,0.03 to 8?g/ml,and 0.06 to 8?g/ml,respectively.Among them,18,19 and 20 have the strongest antibacterial activity.The in vitro bactericidal curves of MRSA were determined on 18,19 and 20,and the three compounds had good bactericidal effect.Among them,the fat distribution coefficients of 18,21 and 23 were 4.86,4.50 and 4.0 respectively.The pleuromutilin derivatives lower than the 2-aminobenzenethiol side chain had a fat-water distribution coefficient of 4.92,and the solubility was improved.