沈阳药科大学《药物化学》PPT教案（英文）_antifungal agents1

Antifungal Agents Fungi are plant-like, nonphotosynthetic eukaryotes growing either on colonies of single cells(yeasts)or in filamentous multicellular aggregetes(molds). Most fungi live as saprophytes in soil or on dead plant materials and are important in the mineralization of organic matter. There are 300,000 kinds of fungi, but only 270 of which produce disease in humans and animals. These fungi are divided into two sections according mycotic illnesses in huamns they produced. That is: shallow fungi, produces skin and hair infections, system fungi, produces visceral infetions. In recent year, the incidence of fungal infections has reached alarming proportions. This duo to a number of factors such as intensive uses of chemotherapies for bacterial infection and cancers. The number of systemic infections have especially increased, this has been true for large populations of immunocompromized patients as well as those

Antifungal Agents Fungi are plant-like, nonphotosynthetic eukaryotes growing either on colonies of single cells(yeasts) or in filamentous multicellular aggregetes(molds).Most fungi live as saprophytes in soil or on dead plant materials and are important in the mineralization of organic matter. There are 300,000 kinds of fungi, but only 270 of which produce disease in humans and animals. These fungi are divided into two sections according mycotic illnesses in huamns they produced. That is:shallow fungi, produces skin and hair infections, system fungi, produces visceral infetions. In recent year, the incidence of fungal infections has reached alarming proportions. This duo to a number of factors such as intensive uses of chemotherapies for bacterial infection and cancers. The number of systemic infections have especially increased, this has been true for large populations of immunocompromized patients as well as those

Suffering from various hematological malignancies, acquired immun deficiency syndrome(AlDs)and patients undergoing organ transplantation So, to develop a new antifungal agents is a very important work. 温暖来件下 面包上的希 旺&且殖

Suffering from various hematological malignancies , acquired immune deficiency syndrome(AIDS) and patients undergoing organ transplantation. So, to develop a new antifungal agents is a very important work

5.1 The classification of antifungal agents Polyenes Amphotericin)B Antimycotic antibiotics: Others (Griseofulvin) Fluorinated pyrimidines(fluorocytosine) Imidazoles (ketoconazole) Azoles Synthetic antifungal Triazoles fluoconazole) Agents: Allyamines (Terbinafine) Thioureas (Tolnafate) Others (Ciclopirox)

5.1 The classification of antifungal agents: Antimycotic antibiotics: Synthetic antifungal Agents: Polyenes ( Amphotericin) B Others (Griseofulvin) Fluorinated pyrimidines (Fluorocytosine) Azoles Imidazoles (ketoconazole) Triazoles (Fluoconazole) Allyamines (Terbinafine) Thioureas (Tolnafate) Others (Ciclopirox)

The classification according to the actions of drugs Acetyl-CoA Squalene Epoxidase +#Ally amines(Thiocarbamates) Lanoste rol ∥- Azoles Cytochrome 14 Demethy llanoster ol P450 Ergosterol +/ Polyenes (Mor phil ines) Cell membranes Griseofulvin DNA Cell nucles Flucytosine ∠-N ucleic ac d

Acetyl CoA Squalene Epoxidase Allyamines (Thiocarbamates) Lanosterol 14 Demethyllanosterol Cell membranes Ergosterol Cytochrome P 450 Azoles Polyenes (Morphilines) Cell nucles Grisofulvin Flucytosine DNA Nucleic acid The classification according to the actions of drugs

5.2 Antimycotic antibiotics 521 Amfotericin B(AMB)(两性霉素B) OH OH OH O HOOC' O OHOH OH oH O H CH NH OH AMB was marked in 1951s, is most commonly antibiotics used to treatment systemic fungal infections and is the only Polyene antibiotic antifungal agents for injection use

5.2 Antimycotic antibiotics 5.2.1 Ampotericin B(AMB)(两性霉素B) O O O OH H HOOC OH OH OH OH OH OH OH O O CH3 OH NH2 OH AMB was marked in 1951’s, is most commonly antibiotics used to treatment systemic fungal infections and is the only Polyene antibiotic antifungal agents for injection use

Mechanism of action of(AMB This kind of antifungal agents act against sensitive fungal by combining with membrane ergosterols with subsequent aeration in permeability and loss of essential organic and inorganic cell constituents In mammalian cell membranes, the principal sterol is chloesterol(Ha 甾醇), AMB binds approximately times more tightly to vesicles(醇囊) containing ergosterol rather than to those containing chloesterol Side-effects The most serious are hypokalemia and distal tubular acidosis. the Nephrotoxicity has been lessened to some extent by lipid complexed formulations

Mechanism of Action of (AMB) This kind of antifungal agents act against sensitive fungal by combining with membrane ergosterols with subsequent aleration in permeability and loss of essential organic and inorganic cell constituents. In mammalian cell membranes, the principal sterol is chloesterol(胆 甾醇), AMB binds approximately times more tightly to vesicles (醇囊) containing ergoesterol rather than to those containing chloesterol. Side-effects The most serious are hypokalemia and distal tubular acidosis. the Nephrotoxicity has been lessened to some extent by lipid￾complexed formulations

Some lipid-complexed formulation of aMB in market and R&D (1)两性霉素B脂质体剂型( AmBisome是用脂质体将两性霉 素B包裹而成已在欧洲和美国上市多年 (2两性霉素B脂质体复合物(ABLC)商品名Abee是脂质体 与两性霉素B交织而成近来已在美国上市 3)两性霉素B胶体分散剂(ABCD.商品名 Amphocil和 Δ mphotec是用等量的硫酸胆固醇与等量的两性霉素混合包 裹现正在欧洲和美国使用 (4)聚乙二醇AMB,AMB/ polethelne glyco- phospholipid脂质, 临床前研究

Some lipid-complexed formulation of AMB in market and R&D (1)两性霉素B脂质体剂型(AmBisome),是用脂质体将两性霉 素 B包裹而成.已在欧洲和美国上市多年. (2)两性霉素B脂质体复合物(ABLC),商品名Abelcet是脂质体 与两性霉素B交织而成,近来已在美国上市. (3)两性霉素B胶体分散剂(ABCD),商品名Amphocil和 Amphotec,是用等量的硫酸胆固醇与等量的两性霉素混合包 裹,现正在欧洲和美国使用. (4)聚乙二醇—AMB, AMB/polethelne glyco-phospholipid脂质, 临床前研究

522 Nystain(NYS)(制霉菌素) OH O OHOH OH OH OH HOOC H' CH3 NH OH OH Deriving from AMB, developed by aronex and in preclinic phase NYS is recommended for treatment of oral thrush or esophagitis caused by Candida albicans in AIDS

5.2.2 Nystain (NYS)(制霉菌素) O O O OH H HOOC OH OH OH OH OH OH OH O O CH3 OH NH2 OH Deriving from AMB,developed by Aronex and in preclinic phase. NYS is recommended for treatment of oral thrush or esophagitis caused by Candida albicans in AIDS

52.3 Griseofulvin(灰黄霉素) OCH3 O OCH3 ≥O CH3O O CH3 Griseofulvin as marked in 1958, the primary site of action of it involves Binding to RNA. Manifestations include inhibition of hyphal cell-wall synthesis and cytoplasmic microtubules. Mainly used to treat the skin fungal infections. The side effects are gastrointestinal, allergic, and more frequently, moderate increase in fecal protoporphyrin

5.2.3 Griseofulvin(灰黄霉素) OCH3 CH3O Cl O O O OCH3 CH3 Griseofulvin as marked in 1958, the primary site of action of it involves Binding to RNA. Manifestations include inhibition of hyphal cell-wall synthesis and cytoplasmic microtubules. Mainly used to treat the skin fungal infections. The side effects are: gastrointestinal, allergic,and more frequently, moderate increase in fecal protoporphyrin

5.2, 4 Others 脂肽类抗生素 Echinocandin OH HO CH3 CH3 NH O(CH2)4CH3 OH HO OH OH 真菌细胞壁具有许多杀真局菌活性的靶位参与真菌细胞壁 的合成的许多合成酶是真菌特有的如1,3-葡聚糖合成酶聚 乙酰氨基葡糖合成酶等

5.2.4 Others OH OH NH NH O HO O CH3 HO O N CH3 HO NH O N OH O OH OH NH O NH CH3 CH3 O O(CH2 )4CH3 脂肽类抗生素 Echinocandin 真菌细胞壁具有许多杀真局菌活性的靶位.参与真菌细胞壁 的合成的许多合成酶是真菌特有的,如1,3-葡聚糖合成酶;聚 乙酰氨基葡糖合成酶等