Synthesis And Antimicrobial Activity Evaluation Of Imidazole-fused Imidazo [2,1-b][1,3,4] Thiadiazole Analogues

At present,the problem of bacterial drug resistance is becoming more and more serious,and the research and development of new drug-resistant bacteria and antimicrobial agents are facing a severe test.In recent years,drug-resistant bacteria spread rapidly and widely around the world.China is one of the countries that abuse antibiotics most seriously in the world,and the problem of bacterial resistance is particularly prominent.In order to resist the abuse of antibiotics caused by bacterial infection and other problems,the pressure on bacteria is increasing,and the frequency of mutation is accelerating.Researchers have found more drug-resistant mutant strains.In terms of fungi,according to incomplete statistics,there are more than 5 million kinds of fungi on the earth,about 300 kinds of which can cause human diseases,among which 20–25 kinds of fungi can often cause diseases.With the use of organ transplantation and various interventional medical methods,the systemic infection caused by Candida is increasing significantly.The frequent use of antifungal drugs leads to the increase of drug-resistant strains,gradually falling into a vicious circle.Therefore,the research and development of new anti drug resistant bacteria drugs is imminent in the face of the severe problems such as the continuous upgrading of bacterial resistance,the weakening of the therapeutic effect of antibacterial drugs,and the lack of clinical treatment.One of the main directions of future research and development is to modify the structure of existing antibacterial drugs or research and develop structures with new targets,which is also an effective way to solve the problem of bacterial or fungal drug resistance.In this paper,three series of 21 novel imidazole derivatives（compounds 20a–g,21a–g and 22a–g）containing imidazole thiadiazole structure were designed and synthesized based on the principle of assembly and isosteric arrangement.Their antibacterial and antifungal activities were evaluated.The results showed that all the target compounds had strong antifungal activity against Candida albicans and high selectivity against gram-positive and Gram-negative bacteria.Compound 21a showed the highest activity against Candida albicans(MIC₅₀=0.16μg/m L),which was 13 times and 3 times higher than that of Gatifloxacin and Fluconazole,respectively.Among them,the compounds（21a and 20e）with better antifungal activity were tested for cytotoxicity and hemolysis.They did not show cytotoxicity to human foreskin fibroblast-1 cells,and compound 21a was as safe as the positive control compound fluconazole in hemolysis tests.These results strongly suggest that some of the compounds produced in this work have value for development as antifungal agents.