Synthesis And Antifungal Activity Research Of GPI-anchored Proteins Inhibitor

With the cancer radiotherapy, chemotherapy, organ transplants, AIDS patients,broad-spectrum antibiotics and immunosuppressive agents, immunocompromisedpatients keep to increase, which result in sharp rise in the incidence of deep fungalinfections. Fungal infections have been one of the leading causes of death for theseabove mentioned patients. On the other hand, with the long-term large-scaleapplication of the antifungal agents, fungal resistance problems become increasinglyserious, and fungi can set up various catheters mycelium or biofilm in the humanbody or the surface of inert materials, to make its drug sensitivity decreased by tens oreven hundreds of times, which attribute to the main reason for failure of clinicalantifungal treatment. In many of the fungal infection patients, the Candida albicansinfection is the most common and typical. Therefore, it is challenging to seek fornovel antifungal drugs. In the field of antifungal agents, heretofore, for instance,amphotericine B which is based on a polyene skeleton, fluconazole,itraconazole andvoriconazole which are based on an azole skeleton, or the like, have been developedfor the treatment of deep seated mycoses. Among pre-existing drugs already availablecommercially are many agents having similar mechanism of action, and currently, theappearance of azole-resistant fungi or the like has been problems.In recent years, as a β-1,3-glucan synthetase inhibitor with a novel mechanism,naturally occurring compound derived cyclic hexapeptides caspofungin andmicafungin or the like, have been developed; however, from the fact that these agentsonly exist in injectable form, they are not yet sufficient practically as antifungalagents.Since there have been the situations that the pre-existing antifungal agents areinsufficient for treatment of the deep seated mycoses, there is a demand and need fordevelopment of agents which are based on a novel mechanism and are of high safety.As the prior art related to antifungal agents based on such a novel mechanism,the researchers are looking for some compounds which demonstrates effects againstthe onset, progress, and persistence of infections by inhibiting the expression of cellwall proteins, inhibiting the cell wall assembly and also adhesion onto cells, andpreventing pathogens from showing pathogenicity, with the process which transportsGPI-anchored proteins to the cell wall being inhibited.GPI-anchored proteins are a class of proteins which is anchored in the surface ofthe eukaryotic cell membrane protein through its carboxyl terminus of theglycosylated-phosphatidylinositol (GPI) structure. Many of such proteins presence incells, which are including the various functions of the proteins, such as the cellsurface enzymes, receptors, adhesion molecules, and specific antigen, etc., playing animmune recognition, complement regulation and transmembrane signal transductionand other important roles. It has been found that GPI is very common way that anchored the surface protein in mammals, fungi, and parasite cell. However,differences in the inositol acylation of GPI in yeast and human cells suggest that thiscould be a good target for drugs directed against yeasts that do not impair inositolacylation in human cells.The destruction of the structure of the GPI anchors or inhibition on itsbiosynthesis would be able to stop and destroy the fungal cell wall assembly, thusinhibit the growth of fungi. Some small molecule compounds, namely E1210,10band Gepinacin, have been reported to inhibit the GPI anchor biosynthesis, therebyinhibit the growth of fungi.Compound E1210is a novel broad-spectrum antifungal agent that inhibits theinositol acylationstep in fungal glycophosphatidylinositol (GPI) biosynthesisresultingin defects in various steps in cell wall biosynthesisleading to the inhibition of cellgrowth, hyphal elongation, and attachment of fungal cells to biological substrates.Although E1210,10b and Gepinacin exhibited excellent antifungal activity, thestudy of SAR and parmacophores on them is rarely reported. In this project,56compounds were designed and synthesized, with10b as a leading compound. Theantifungal activity against Candida albicans was determined in vitro. The compoundGPI-27is the most active compound among the derivatives with a MIC80of0.125g/ml, which is comparable to the lead10b. The preliminary SAR on the compoundsshowed that the2-amino-3-formide motif is the pharmacophore of this kind of agent.The substitution of amino group with hydroxyl, F, or H may result in the total loss ofantifungal activity. The substitution of the formide with sulfonamide also caused theloss of activity. Moreover, N-(2-aminopyridine-3-formyl)-substituted anilinederivatives exhibited good antifungal activity, which deserve further research.