Synthesis And Biological Evaluation Of Novel Pleuromutilin Derivatives

Since the discovery of sulphonamide antibiotics and penicillin in 1930,the fatality rate associated with bacterial infections was significantly decreased.With the increasing use and even abuse of antibacterial drugs,the spread of resistance to existing antibiotics became a major concern in medical community.To develop new antibacterial agents that possess a novel mechanism of action and display minimal cross-resistance with existing drugs,more and more attention are focused on the structure modification of pleuromutilin.In 1951,Kavanagh first isolated Pleuromutilin from pleurotus mutilus and pleurotus passckerianus.It was characterized as antibiotic with modest in vitro activity against Gram-positive bacteria and mycoplasmas.Based on SAR studies and the structure modification of pleuromutilin,tiamulin and valnemulin were successfully developed as the veterinary antibiotic medicines.Retapamulin was developed as a topical antimicrobial agent for human use.This class of antibiotics selectively inhibited the synthesis of bacterial protein by interaction with the 50 S bacterial ribosome subunit.The specific interaction leads to the difficulty of pleuromutilin to produce cross resistance with other antimicrobial agents.We synthesized 15 new thioether pleuromutilin derivatives based on Wang’s designed derivatives processing aminothiazole group at C14 side chain as lead compound by thiazole acylation of amino with a series of substituted benzoic acids and heterocyclic carboxylic acids and amino acids under mild conditions.The hydroxyl of C14 side chain was turned into thiol,then thiol substituted derivative reacted with electrophile to afford 2 new derivatives.The antibacterial properties of the prepared pleuromutilin derivatives were assessed in vitro by the broth dilution method against MSSA,MSSE,MRSA,S.agalactia,Pyogens and Mycoplasma gallisepticum(MG).And we evaluated the MICs of part of derivitives against resistant bacterial.All of the tested compounds displayed moderate to good antibacterial activities.However,the activity of these new compounds to Pyogeniccoccus was generally poor to the control drugs.Compound 6j and 6l showed potent antibacterial activities which were better than that of Vanemulin.