Design,Synthesis And Bioactivity Evaluation Of New Cationic Antibacterial Amphiphiles

Antibiotics are the most successful chemotherapeutic drugs in the history of drug treatment.They are not only used for the treatment of clinical infectious diseases,but also provide a guarantee for clinical surgery and postoperative anti-infective treatment.However,the continuous development of bacterial resistance and stagnation of antibacterial drug research have led to the failure of more and more antimicrobial compounds.Studies have found that some small molecule cationic antibacterial peptide mimics have good antibacterial activity and no drug resistance.Therefore,we need to develop novel compounds with new antibacterial mechanisms(high antibacterial activity,low cytotoxicity and low resistance).In order to find a breakthrough point to solve these questions,we have accomplished the following work based on the previous literature research.1)We have synthesized 21 dialkyl cationic antibacterial peptide mimics,then antibacterial activity of these molecules were evaluated.The minimal inhibition concentration(MIC)of this series of molecules have been tested against gram-positive and gram-negative bacteria.And the results indicate that several compounds have excellent antimicrobial activity.These active compounds were tested for the activity against drug-resistant bacteria(MRSA,KPC and NDM).We have selected compound 2-4g to evaluate antibacterial mechanism,cytotoxicity,hemolytic ability,mammalian fluid stability,bactericidal dynamics and the propensity to induce drug resistance.The results of all experiments indicate that compound 2-4g can be used as a potential antibacterial agent with positive charges and amphiphilicity and need a further study.2)In this paper,we have synthesized 16 deacetyl linezolid derivatives and the antibacterial activity of this series of compounds have been evaluated against various gram-positive and gram-negative bacteria.Then we have selected several molecules with better antibacterial activity to test for the activity against drug-resistant bacteria.Moreover,compound 3-6e was evaluated antibacterial mechanism,cytotoxicity,stability and so on.It was obviously to find that compound 3-6e can be used as a potential and broad spectrum antibacterial agent.3)Bioactivity of a series of cationic chalcone compounds that mimic the essential properties of cationic antimicrobial peptides were designed and evaluated.Antibacterial activities against drug-sensitive bacteria and drug-resistant species were determined.Compounds 4-5a and 4-5g showed good bactericidal activity.These membrane-active compounds demonstrated the ability to effectively bring down viable counts in bacterial biofilms and don't induce the development of resistance in bacteria.And these compounds were evaluated antibacterial mechanism,cytotoxicity,stability and so on.To sum up,we have designed three series of cationic amphiphilic antibacterial compounds,and established a relatively complete evaluation method of in vitro biological activities.Moreover,a platform for the evaluation of small peptides in vitro biological activity was initially set up.This can perfectly evaluate bacteriostasis,sterilization,stability,cytotoxicity and bactericidal mechanism of small molecule modeling peptide.