Synthesis And Antimicrobial Activity Evaluation Of Pyrazole Derivatives Containing Imidazo [2,1,b][1,3,4] Thiadiazole Moiety

At this stage,the problem of bacterial drug resistance is becoming more and more serious,and the drug-resistant bacteria have spread rapidly and widely all over the world in recent years,which leads to the severe test of the research and development of new drug-resistant drugs.According to incomplete statistics,there are more than 5 million kinds of fungi on the earth,and about 300 kinds of fungi will cause human diseases,of which 20-25 kinds of fungi will often lead to diseases.Fungal infections occur in more than a quarter of the world’s population,but the huge burden caused by fungal infections is underestimated.Most fungal infections are superficial and easy to treat.However,fungi can also cause invasive diseases associated with more than 50%mortality,killing an estimated 1.5 million people a year.However,the treatment of fungal infection,especially invasive fungal infection,is facing great challenges.The change of fungal infection types and the acceleration of fungal variation lead to the increase of drug-resistant strains.The types of antifungal drugs that can be used in clinic are limited and have obvious disadvantages,which are far from meeting the treatment needs of fungal infection in clinic.Therefore,the discovery of antifungal lead compounds with novel structure,high efficiency and low toxicity is of great significance for the development of drugs for the treatment of invasive fungal infection.At present,we can solve this problem from three aspects:① finding new antifungal drug targets and studying the relationship between the mechanism of fungal resistance and the application of antifungal drugs.②Develop new skeleton compounds or introduce other antifungal mechanisms into existing advantageous targets.③Structural transformation of existing drugs.Obviously,the latter two are economic and practical drug research strategies with short development cycle.In our preevious research work,it was found that a series of compounds containing imidazo-thiadiazole and imidazole-centered rings in their structures had good antifungal activity and showed high selectivity in fungi and Ggram-baciillus.In this paper,four series of 40 new pyrazole derivatives(29a-m、30a-m、31a-g and 32ag)containing imidazole thiadiazole structure were designed and synthesized based on the principle of assembly and electronic isosteric arrangement of new drug design.Their antibacterial and antifungal activities were evaluated for 7 kinds of bacteria and fungi.It is further investigated whether this kind of structurally novel compounds also possess excellent antifungal activity and high selectivity.Most of the synthesized compounds showed no or low inhibitory effect on Grampositive and Gram-negative bacteria,while individual compounds 29e(MIC=16μg/mL)、30b(MIC=16 μg/mL)、30e(MIC=16 μg/mL)、30i(MIC=8 μg/mL)and 32g(MIC=16 μg/mL)showed moderate inhibitory activity on Gram-positive bacteria 209.In addition,most compounds showed no or weak inhibitory activity against two drug-resistant bacteria,while a few compounds(30b,30g,31a,31b,31e,32a,32b,32f,and 32g)only showed moderate or strong inhibitory activity against MRS A 3167.Among them,compound 32a(MIC=2 μg/mL)showed the strongest inhibitory activity on MRS A 3167,and its activity was equal to that of Gatifloxacin.In terms of antifungal activity,most of the target compounds(29a-m、30e、30gm、31b-g and 32e-g)showed moderate to strong antifungal activity against the fungus Candida albicans 7535(MIC=0.25-16 μg/mL).Among the 29 series compounds,all compounds showed strong antifungal activity(MIC=0.25-1 μg/mL),and the activity of these compounds was similar to or higher than that of Gatifloxacin(MIC=0.5 μg/mL)and Fluconazole(MIC=1 μg/mL).More than half of the 30 series compounds(30e and 30g-m)showed moderate to strong antifungal activity(MIC=116 μg/mL).Among them,compounds 301(MIC=1 μg/mL)and 30m(MIC=1 μg/mL)showed the strongest antifungal activity,and their activity was the same as that of Fluconazole.Among the 31 series compounds,all compounds(31b-g)showed strong antifungal activity(MIC=2-8 μg/mL)except unsubstituted compound 31a(MIC=32μg/mL).Among them,compounds 31f(MIC=2 μg/mL)and 31g(MIC=2 μg/mL)showed the strongest antifungal activity,which was similar to Fluconazole.Of the 32 series compounds,only three compounds(32e-g)showed moderate to strong antifungal activity(MIC=2-16 μg/mL).Among them,compounds 32f(MIC=2 μg/mL)and 32g(MIC=2 μg/mL)showed the strongest antifungal activity,which was similar to Fluconazole.Among all compounds,compounds 291(MIC=0.25 μg/mL)and 29m(MIC=0.25 μg/mL)showed the strongest antifungal activity,which was two and four times higher than that of Gatifloxacin and Fluconazole,respectively.Noteworthy,most of compounds showed strong antifungal activity and showed high selectivity to both Gram-positive and Gram-negative bacteria,confirming the previous hypothesis.Through the research of this paper,a variety of compounds with strong antifungal activity were found,and the relationship between structure and activity was clarified.This study provides experimental and theoretical basis for the research and development of this kind of antifungal drugs containing pyrazole moiety.