The Structure-activity Relationship Of Antifungal Triazoles And Disulfides And "Azole-ethyl-heteroatom"Hypothesis

FungaI infection, esPecial1y systemic fungal infection, in hUInan has beenincreasing. Itnmuncompromised patients who have received cancer chemotheraPy andirnmunosuPpressive theraPy for organ traIisPlans, patienis under long-term treaneni withbroad-spectruIn antibiotics or glucoconicosteroids, and patient with AlDS are particularlysuscePtible to fungal infections. Candde spp., CmptOccocus neOformans, and AsPehalIusfumguts are three major pathOgens that cause opportunistic fungal infection. Anidrigaldrugs with high potency are scarce in the past, but major developments in research intothe azole class of antifungal agents during the l990s have provided exPanded options forthe treatment of many supefficial and systemic fungal infections, such as Fluconaxole andItranconazole, which proved to be safe and effchve, and are reconuneded as the fustchoice of the anifungal drugs fOr treating fimgal infections. Nowadays, azole comPoundsare the most widely and deePly stUdied class of antifungal agentS. DesPte the advances,serious fimgal infections remain difficult to treat, and resiStance to the available trigs isemerging. Howevef, azoles have the drawacks of side effects, including hePatotoxicityand limited antifungal spectrum. Accordingly, the discovery of antifungal agents thatpossess high potent and low toxicity remains an importan chanllenge.Azole (imidazole and triazole) anigungal agents have been shown to iambit theergosteroI biosynthesis of fungi, which is an imPOrtant constitUent of the drigal cell Wall,and also has a hormone-like fimction in fungal cells, which stimulates growth and,proliferation. An important step in ergosterol biosynthesis is the l4(demethylation oflanosterol, mediated by the cytochrome P450 monooxygenase enZyIne. The l4 Q -methylgroup of Ianosterol is removed via three oxidation steps by sequenhal attacks of theoxygen atoms coordinated with the protoheme iron atom located in the binding domain ofthe enZyme. Inhibihon of thes enZyme is believed to be brough about by a mechbosm inwhich azole anifungals bind to the heme iron atom with the lone pair eleCtrOns of the ringnitrogen atomN-3 of imidazole and N-4 of triazole) and exclude oxygen which wouldnormally take part in the reaction.The strucfore-activity relationships seen with azoles suggest that azole cycle and2,4-difiuorophenyl moiety are essential fimctional groups for potent antifimgal achvityAccording to the research of the target enZyme lanosterol l4 Q -demethylase (P4 5 0l4ov orCYP5l), as well as our previous research on azoles, we suggest that the hydroxy grouP ofthe tertiary alcohol is also very importan to their anifungal activity besides azole cycleand 2,4-difluorophenyl moiety Thus, we have designed and synthesized 64 l-(lHl,2,4-triaZol-l-yl)-2-(2,4-difluoroph In the for of thetitle comPounds, l-(lHl,2,4-triaZol-1-yl)-2-(2,4 propanols, is thecomrnon basic structUre, with Which different side chain is connected by S and O atom atthe 3-position. The main aim of us is to research the influence of the side chains to theantifungal activity. The strUctures of the title compounds were determined by elementalanalysis, 'HNMR, IR, and MS. Preliminary anifungal activity in vitrO of the comPoundswere examined by brOth macrodilution test against Candde albican4 CryPtOcoccusneOfOrmans, Candida mpicalis, Candde paraPsiIosis SPorothrir schenckii, FOnsecaeapedrOsol; TrichOPhyton rubrum, AsPergillus fumdetus. l6 compounds showed highpotent in vitrO activity against the 4 Candida sPp., the MIC8os of which are less than0. l25 u g/mL, also showed somewhat activity against other tested fimgi. According to thestructUres and anifimgal activities of the title compounds, we have made suchconclusions on properties of the 3-position side chain:1. The side chain which goes straightly on the whole can enhance anifimgal activityof the compound.2. Changing the positions of WH- and --CO- with each other makes no diffeence of...