Synthesis And Biological Evaluation Of Quinolinone Derivatives As Potential Antibacterial And Anti-inflammatory Agents

Since the 21st century,the issue of bacterial resistance in the global context was increasing serious.According to the British Prime Minister's Economics Adviser's report,by 2050,if the drug resistance is not curbed,there will have 10 million people died of drug-resistant infections each year,and annual economic losses will be reached as high as 100 trillion dollars in the world.In China,the problem of bacterial resistance is equally serious.Unfortunately,the development of new antibiotics does not satisfy the increase of drug-resistant bacteria.Multidrug-resistant infections,coupled with the lack of new antimicrobial agents,have led clinicians to reconsider the use of polymyxin as a final treatment,and this drug have not been used clinically for many years due to its neurotoxicity and nephrotoxicity.Therefore,it is an ongoing demand for new antibacterial agents.Inflammation is a common pathophysiological phenomenon involved in many diseases and is the most primitive protective response of the body to noxious stimuli.Inflammation is a serious threat to human health in allergic reactions,autoimmune diseases and organ transplant rejection.Treatment of acute and chronic inflammation by non-steroidal anti-inflammatory drugs has been very common,but their long-term use will produce some adverse reactions,such as bone tissue damage,gastrointestinal injury,liver damage,toxic kidney injury.Therefore,the development of novel anti-inflammatory agents is crucial for ongoing effective therapeutic intervention.Quinolines occupy a unique position in heterocyclic chemistry and present a key motif in medicinal chemistry because of their capability to exhibit a variety of biological activities such as antimicrobial,anti-tumor,anti-HIV,and anti-inflammatory activities.In recent years,aminoguanidine and hydrazone derivatives have been infrequently used in antibacterial and anti-inflammatory agents.In this work,as part of our ongoing studies toward the development of novel anti-inflammatory agents,we designed and synthesized new hybrid 3,4-dihydroquinoline derivatives bearing aminoguanidine or hydrazone moieties,and evaluated for their in vitro antibacterial activity and in vivo anti-inflammatory activity using xylene-induced ear-edema model in mice,respectively.Among three series of compounds,only compounds in series 5 have better antibacterial activity against Gram-positive bacteria and fungi than that against Gram-negative bacteria,with MIC values of 1-64?g/mL.Compounds in series 5 against the clinical multi-drug resistant bacteria also showed a strong antibacterial effect,with MIC values in the range of 1-64 p.g/mL.Among them,compounds 5c,5d and 5k showed the strongest activity with MIC values of 1 p,g/mL.Compounds in series 5 showed the highest activity with MIC value of 1?g/mL against MRSA CCARM 3506,showed the same potency as moxifloxacin(MIC = 1?g/mL)and more potent activity relative to gatifloxacin(MIC =2?g/mL).For QRSA CCARM 3505 and 3519,most compounds in series 5 exhibited 4 to 8-fold more potent activity relative to gatifloxacin and moxifloxacin(MIC = 4-8?g/mL)with MIC value of 1?g/mL.The results of anti-inflammatory test revealed that most of the synthesized compounds showed significant effects.It is noteworthy that compound 5a exhibited the most potent activity of all of the compounds with an activity of 94.01%,which was higher than that of ibuprofen(39.56%)at 100 mg/kg(i.p.).The activity of compound 5a reached its peak at 3 h when administered orally,showed a maximal effect with an ear inflammation inhibition rate of 47.32%at 50 mg/kg and was found to be more potent than ibuprofen at the time point(44.13%).While the inhibition rate of 5a was significantly decreased when administered orally,indicating that the degree of oral absorption of the compound 5a was lower than that of ibuprofen.