Synthesis And Evaluation Of Antifungal Activities Of Novel Triazole Derivatives Containing Sulfur Atoms

In recent years,fungal infections are common clinical diseases with high morbidity rates.Superficial fungal infections(involving the skin and mucosal surfaces)that is not life-threatening account for more than 90% of fungal infections and reduce quality of life highly.With the improvement of medical level,the prevalence of invasive fungal infections has increased sharply,especially in the treatment of critical patients(those involving chemotherapy,radiotherapy,dialysis,corticosteroids,broad-spectrum antibiotics,parenteral nutrition,iv.catheter,organ transplantation and other major surgery).Furthermore,the increased incidence of AIDS made deep fungal infections to be a major potential disease.Recently,deep fungal infection has been known as a kind of serious illness with high morbidity and mortality.The development of antifungal drugs behind that of antibacterial agents is due to lack of awareness about the incidence and consequences of fungal infections.Because of evolutionary similarities between fungi and humans,few differential targets for antifungal drug is the reason of insufficient selectivity and more side effects of antifungal drug in clinic.There are five classes of antifungal agents(polyenes,allylamines,azoles,pyrimidine analogs and echinocandins)for the treatment of fungal infections.Because of broad antifungal spectrum of Amphotericin B(AmB),it is the most widely used antifungal agent for treatment of fungal infection.The toxicity of AmB can causes impairment of renal function.Flucytosine,with narrow antifungal spectrum,occurs drug resistance easily and has a lot of side effects.Triazole drugs,representative drugs such as Fluconazole,Itraconazole and Voriconazole,are the first-line antifungal agents for treatment of fungal infection.They show extraordinary effects to treat invasive fungal infections for its highly efficient,broad spectrum and good oral bioavailability.The occurrence of drug resistance and its nephrotoxicity and hepatotoxicity limit application of triazole drugs in clinic.Therefore,it is necessary to develop new safe and effective antifungal compounds with broader spectrum.Based on the further research for antifungal mechanism and chemical construction of Fluconazole,Two series of novel compounds were synthesized by retaining the three basic pharmacophores of Fluconazole(1,2,4-triazole,2,4-difluorophenyl,and tertiary alcohol structure).Intermediate 5 was prepared by ring-opening reaction of the key intermediate 4 and propylamine.The series of compounds A were synthesized from intermediate 5 which reacted with carbon disulfide and various substituted benzyl bromide by one-pot procedure.Intermediate 6 was prepared by ring-opening reaction of the key intermediate 4 and N-Boc-piperazine.Intermediate 7 was obtained through the deprotection reaction of intermediate 6.The series of compounds B were synthesized from intermediate 7 which reacted with carbon disulfide and various substituted benzyl bromide by one-pot procedure.The in vitro antifungal activities of all title compounds were evaluated with broth dilution method recommended by the National Committee for Clinical Laboratory Standards(NCCLS)against eight human pathogenic fungi(Candida albicans SC5314,Cryptococcus neoformans,Candida parapsilosis,Candida glabrata,Trichophyton rubrum,Microsporum gypseum,Candida albicans Y0109,Aspergillus fumigatus).The series of compounds A and B showed potent antifungal activities.