Design, Total Synthesis And Antifungal Activity Of Noval Echinocandin Type Cyclohexalipopeptides

Past decades have witnessed a dramatic rise in morbidity and mortality of fungal infections, especially deep, systemic fungal infections, with has seriously threatened to human health. This is mainly due to the rapid increase of immunocompromised patients caused by organ transplants, cancer chemotherapy and radiotherapy, the overuse of antibiotics and the AIDS epidemic. Drug interactions, drug side effects, and easy to produce drug resistance and other problems of the current efficient antibacterial agents such as azoles and polyene are widespread. Therefore, there is an emergent demand for the discovery of antifungal drugs with new mechanisms, new targets and highly selection to fungal cells.β-1,3-glucan which is catalyzed by P-1,3-glucan synthase (GS) is an important component of the cell wall of many pathogenic fungal cells. Therefore, the inhibition of the GS could block the synthesis of glucans, so that the fungal cell wall defects and eventually lead to fungal cell death. Because GS is not existed in human bodies, GS inhibitors have a selective effect to fungal cells, and have become a research focus in recent years.With a strong inhibitory activity to Candida and Aspergillus, natural echinocandins has exhibited a narrow antimicrobial spectrum, poorly water-soluble, hemolytic toxicity and other defects. A number of semi-synthetic derivatives of natural echinocandins have entered clinical studies, including caspofungin, micafungin, and anidulafungin, which have been listed in the United States and Japan, respectively.Considering the drawbacks of natural echinocandin type cyclohexa lipopeptide compounds as well as the limitations of their semi-synthetic studies, in the support of the National Natural Foundation of China (30930107) and NSFC (30772674), we dedicate our efforts to carry out design, total synthesis, and derivative work of new type of cyclohexa lipopeptide compounds, to further explore the structure-activity relationship of these compounds, and looking for efficiency and low toxicity antifungal lead compound.1. the total synthesis of cyclohexa lipopeptide compounds with a novel lopophilic side chain1.1the total synthesis of cyclohexa lipopeptide compounds with a lipophilic side chain of4-(1-alkyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl) benzoylConsidering the narrow antifungal spectrum, poorly water-soluble and hemolytic toxicity of natural echinocandins, as well as the limitations of their semi-synthetic studies, and based on the known structure-activity relationship of these compounds, we design and total synthesized16new type cyclohexa lipopeptide compounds (series A) though a liquid [3+3]-segment coupling strategy. In vitro antifungal activity studies have shown that:most of the compounds exhibited poor in vitro antifungal activity; several compounds such as A3～A4, A11～A12exhibited moderate inhibition activity especially to C. alb.(Y0109) and C. alb.(SC5314); all compounds exhibited some inhibition activity to C. neo., A. fum. and T. rub.. Preliminary structure-activity relationship of this series of compounds showed that, the introduction of free amino on the left side, threonine residues on the right side and the extension of the lipophilic side chain of this series of compounds could improve its antifungal activity.1.2the total synthesis of cyclohexa lipopeptide compounds with a lipophilic side chain of4-(3-(4-(alkoxy)phenyl)-1,2,4-oxadiazol-5-yl) benzoylA series of novel compounds (series B) with a lipophilic side chain of4-(3-(4-(alkoxy) phenyl)-1,2,4-oxadiazol-5-yl)benzoyl was designed and total synthesized via bioisosterism of the lipophilic side chain of micafungin, combined with the design of compounds of series A. In vitro antifungal activity studies have shown that:most of the compounds exhibited in vitro antifungal activity. The inhibitory activity of compounds B3, B4, B7and B8to C. neo., A. fum. and T. rub. is better than cospofungin. The structure-activity relationship of series B is similar to that of series A.2. the synthesis of double glycosylation cyclohexa lipopeptide compoundsThe echinocandin type cyclohexa lipopeptide antifungal agent is a noncompetitive inhibitor of the GS, so the binding site of this type compounds to GS may be different from that of GS substrate (UDPG). To this end, we designed and synthesized the double glycosylation cyclohexa lipopeptide compounds (series C), which are expected can simultaneously act on the two binding sites of GS. Total16double glycosylation cyclohexa lipopeptide compounds were synthesized, and their in vitro antifungal activity was tested.In vitro antifungal activity studies have shown that:all compounds exhibit poor antifungal activity; several compounds such as C1～C3, C9～C11and C13exhibit moderate inhibition activity to C. alb.(Y0109) and C. alb.(SC5314), compounds C10and C11also exhibit moderate inhibition activity to C. gla. and T. rub.; the in vitro antifungal activity studies further validate that the left amino of cyclohexa lipopeptide act an active role to their in vitro antifungal activity.The reason of the poor in vitro antifungal activity of these compounds may be like the following:left biscarbamic position of cyclohexa lipopeptide may be associated with the interaction of the target enzyme; the molecular is too large to bind with the target enzyme; the linker of the sugar with cyclohexa lipopeptide is not proper, that cyclohexa lipopeptide and the sugar molecules could not get into their respective bindings of the target enzyme.