Synthesis And Antimicrobial Activities Of Novel Fluorotriazoles

Research and development of triazoles as antimicrobial agents have become one of active fields in medicinal chemistry. This thesis based on the current situation of triazoles as antifungal and antibacterial agents, designed and synthesized a series of novel ether and amino fluorotriazoles by reduction, etherization, and quaternization and so on starting from commercial 1-(2,4-difluoro phenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone 18, and evaluated in vitro for the antifungal and antibacterial activities of the new synthetic compounds. Some reaction conditions and structure-activity relationships were also discussed.The synthesis of novel ether fluorotriazoles started from commercial triazolone 18. The later was reduced with sodium borohydride to afford the triazolyl alcohol 19 in high yield. Then the intermediate 19 reacted with respectively a series of alkyl halides to afford the desired aliphatic ether fluorotriazole 20, alkyl dihalides to give the haloalkyl fluorotriazole 22, halobenzyl halides to yield aralkyl fluorotriazole 24. The fluorotriazoles 20, 22 and 24 were treated by nitrate acid to afford the corresponding nitrate salts 21, 23 and 25. The ether fluorotriazole 24 was quaternized by halobenzyl halides to give the desired fluorotriazolium 26. The desired novel amino fluorotriazoles were prepared from the nitro compound 24g. The catalytic hydrogenation of nitro fluorotriazole 24g in methanol using Pd/C as catalyst gave amino fluorotriazole 27. Compound 27 was condensed with a series of halobenzyl halides to afford the desired amino compounds 28 and 29 respectively. All the synthetic new compounds were confirmed by IR, 1H NMR, 13C NMR and/or MS.The reduction condition of triazolone 18 was improved and the target compound 19 was obtained successfully in higher yield. The reaction conditions of halides with respectively triazolyl alcohol 19 and fluorotriazole amine 27 were explored, and the results showed that the temperature, halide and its concentration were three important factors for the synthesis of target compounds.The antimicrobial activities in vitro showed that all the synthetic new fluorotriazoles displayed potent activities against fungi. Some fluorotriazoles also showed good activity against bacteria. Especially, compounds 24a, 24d, 24e, 25a, 25d, 29a and 29b showed better activity against C.albicans than fluconazole which is being used in clinic. Among tested compounds, fluorotriazole 21b, 25a, 25c and 28a showed the strongest activity against A.fumigatus. Compounds 21d and 29b had better activity against S.aureus than amphemycin using in clinic and get close to the norfloxacin. Compounds 21b, 28d and 29b also showed better activity against P.aeruginosa than amphemycin and get close to the norfloxacin. Compounds 21b, 25d and 29b gave stronger activity against B. subtilis than amphemycin and get close to the norfloxacin. Compounds 24e, 28c and 28d gave stronger activity against B.proteus than amphemycin and get close to the norfloxacin. Compounds 21a and 21b showed better activity against E.coli than amphemycin and get close to the norfloxacin. These compounds are promising for further research and development as antimicrobial agents.The structure-activity relationships showed that haloaryl fluorotriazoles had the better antimicrobial activities than other groups, and the position of halogen atoms in aryl ring possess important to antimicrobial activities; the fluorotriazoles with short alkyl chain gave better activities than long ones; haloalkyl fluorotriazoles had stronger activies than non-haloalkyl derivatives. The fluorotriazoliums possess good stability and gave better antimicrobial activies. The secondary amine-type fluorotriazoles displayed lower activities than tertiary amine-type derivatives.In this thesis, 40 Compounds were successfully synthesized. Among these synthetic compounds 39 fluorotriazole derivatives were new, including 16 fluorotriazoles, 15 fluorotriazole nitrate salts, 1 fluorotriazolium, and 8 amino fluorotriazoles.