Synthesis And Antifungal Activity Research Of GPI-anchored Proteins Inhibitor

Fungi are a prominent cause of hospital-acquired infections that are becomingincreasingly difficult to control. This disturbing trend is driven by the growingnumber of severely immunocompromised individuals in the population that hasoccurred as a result of advances in the management of cancer, organ transplantation,autoimmune disorders, and HIV. Most fungus-related morbidity and mortality iscaused by the pathogens Candida albicans and Aspergillus fumigatus, which remaincostly to treat and extremely difficult to eradicate in the immunocompromised host.Candida species are currently the fourth leading cause of hospital-acquiredbloodstream infection and kill up to40%of their victims, while disseminatedAspergillus infections kill up to80%of the patients they afflict.In the field of antifungal agents, heretofore, for instance, amphotericine B whichis based on a polyene skeleton, fluconazole, itraconazole and voriconazole which arebased on an azole skeleton, or the like, have been developed for the treatment of deepseated mycoses. Among pre-existing drugs already available commercially are manyagents having similar mechanism of action, and currently, the appearance ofazole-resistant fungi or the like has been problems. In recent years, as a1,3-β-glucansynthetase inhibitor with a novel mechanism, naturally occurring compound-derivedcyclic hexapeptides caspofungin and micafungin or the like, have been developed;however, from the fact that these agents only exist in injectable form, they are not yetsufficient practically as antifungal agents. Since, there have been the situations thatthe pre-existing antifungal agents are sufficient for treatment of the deep seatedmycoses, there is a demand and need for development of agents which are based on anovel mechanism and are of high safety.The biosynthesis of GPI anchors in fungi was frst proposed as a potentialantifungal drug target by Tsukahara et al. Glycosylphosphatidylinositols (GPIs) areglycolipids that play a role in attaching cell surface proteins to eukaryoticplasmamembranes, including those in fungi. Fungal pathogens are thought to utilizetheir cell wall glucan-anchored mannoproteins to initiate the binding to target tissuesand begin the process of invasion. GPI-anchored proteins play important roles in cellwall biosynthesis and maintenance of homeostasis. As GPI-anchored proteins are oneof the major cell wall components of eukaryotic microorganisms, it may be possibleto design drugs that target this biosynthetic pathway in fungi without causing adverseeffects in human cells. Although the aminopyridine derivatives, which target the Biosynthesis of GPIanchors have very impressive activity against fungal, their Structure–activityrelationship studies still not been reported. Taking the reported active compound10bas a lead, we decided to design amino pyridine derivatives using bioisosterismstrategy in order to study the SAR and optimize the structure. Bearing the aminopyridine motif as in10b.45derivatives were designed and sorted by the types of Aring in three categories. A ring is replaced by thiophene in the series C, furan in theseries D, and benzene in series E. The preliminary SAR were discussed in this thesis.In general, the series C exhibited more antifungal activity than the series D and E.Among them, compounds8d,8f,41a,41d and41e exhibited potent activity againstCandida albicans especially8d,8f,41d showed comparable activity to10b andE1210. These newly synthesized compounds are first reported by our group and theirstructure were confirmed by LC-MS and HNMR.