Synthesis And Antifungal Activity Of Novel Triazole Compounds

As the broad-spectrum antibiotics and immunosuppression widely used in patients, and the emerging of chemotherapy on tumor and organ transplantation and AIDS, the number of immunosuppressive patients is increasing. The morbidity and mortality of fungal infection takes on ascend trend in recent years. The research of the systemic antifungal agents is one of the research hotspot in anti-microbial agents, especially drugs treating deep fungal infection.Despite the availability of Amphotericin B, Fluconazole and Itraconazole antifungal therapies, morbidity and mortailty from invasive fungal infections remain unacceptably high. In addition, many of the currently available antifungal agents have limitations, including toxicity, fungal resistance and the treatment of some fungal infections, particularly Aspergillus fmigatus, is still far from satisfactory. Therefore, it is a critical need for new antifungal agents that are more potent, broader spectrum, and higher effective, yet safe and well tolerated.Azoles is an important class of antifungal agents that interfere with ergosterol biosynthesis by inhibiting a cytochrome P450 enzyme lanosterol 14αdemethylase (CYP51), an essential enzyme in this pathway. This leads to the depletion of ergosterol and accumulation of C-14 methylated sterols and hence disruption of membrane functions. Triazole antifungal agents such as Fluconazole and Itraconazole now are the most widely used for the treatment of systemic fungal infections.In an effort to search for more potent, less toxic and broader spectrum antimycotics, sixty-four 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substi- uted-2-propanols were designed and synthesized according to the antifungal mechanisms and structure-activity relationships of the azoles antifungal compounds. The pharmacophores including triazolely, 2,4-difluorophenyl and 2-propanol were remained and while ethoxycarbonylmethyl, substituted triazolely, substituted piperazinely and hydramine were inducted. after a series of reaction, the target compounds A1-A8 were synthesized with different hydramine. The synthesis of compound 7 is very key to synthesis the class of compounds. The target compounds B, 1-(1H-1,2,4-triazole-1-ly)-2-(2,4-difluorophenyl)-3-N-ethoxycarbonylmethyl-N-substi-uted-1,3,4-triazolely-2-propanols, were synthesized through substituted reaction, cyclization reaction. In the synthetic route of compounds B, the synthesis of the compound 9 is of the greatest importance, and it is effective for forming triazole that DMSO as solvent and ascorbate sodium (Vc-Na) and copper sulfate in a litter water as catalyst. The target compounds C were synthesized from 1-(1H-1,2,4-triazole-1-ly)-2-(2,4- difluorophenyl)-ethanone via Barbier-Type reaction, cyclization and amination. It is a difficulty for the synthesises of compounds C, D and E that intermediate compound 10 was obtained and the phenylethanone was completely disappearance in reaction , because the Rf value of intermediate compound 10 is same as phenylethanone in TLC. Via Barbier-Type reaction, cyclization, hydrolysis reaction to carboxylic acid and active ester reaction with substituted piperzine, the title compounds D were obtained. The target compounds E were design and synthesized. In the synthetic route of compounds E, it is important that asking to selectively react with carbinol, and the hydroxy in quarernary carbon wasn't of elimination. Under appropriate conditions, it is desirable condition that NaH was used as base under 0℃for one hour. All the title compounds were first reported and confirmed by means of 1H-NMR and LC-MS.MICs of all the title compounds were determined by the method recommended by the National Committee for Clinical Laboratory Standards(NCCLS) using RPMI1640 test medium. Eight fungi were used: Candida albicans SC5314, Cryptococcus neoformans ATcc56992, Candida parapsilosis, Candida tropicalis, Trichophyton rubrum, Candida kefyr, Candida albicans Y0109, Aspergillus fumigatus.The results of preliminary antifungal test showed that all title compounds exhibited potent antifungal activities against eight the pathogenic fungis, especially against deep fungal infection. Compound 8 showed high activities against Candida albicans Y0109, Candida kefyr and Cryptococcus neoformans ATcc56992 compared with fluconazole and amphotericin B. The introducing of ethoxycarbonyl-methyl and substituted triazolyl displayed a decreased activity as a result of the spase structure. Besides, Compounds with the groups of alkylol amine had a disadvantage for the compounds passing through the cellmembrane due to the increased polar, which decreased the activity dramatically. These results may provide some guidance for the development of novel triazole-based antifungal lead structures. Further structure-activity relationship studies are worth to discuss.