Medicinal chemistry of Antifungal agents
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Introduction of pathogenic Fungi,Chemical Classification of antifungal agents,SAR and structure of antifungal agents and Synthesis of Antifungal drugs
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Medicinal chemistry of Antifungal agents
- 3. 3 THE FUNGI KINGDOM Mycology - the study of fungi fungi - singular fungus - plural 1) fungi are eukaryotic •they have a nuclei & mitochondria 2) they are heterotrophs •they depend on other organisms for food 3) they are multicellular 4) they cannot move on their own 4 Main Characteristics of Fungi 1. OVER VIEW OF FUNGAL Mr.Ganesh D.Mote
- 6. 1). CANDIDA Candida species cause infections in individuals with deficient immune systems. Th1-type cell-mediated immunity (CMI) is required for clearance of a fungal infection. 6 2. TYPES OF FUNGAL INFECTIONS CANDIDA INFEC TIONS
- 7. 7 2). ASPERGILLUS •The most common pathogenic species are Aspergillus fumigatus and Aspergillus flavus. Aspergillus flavus produces aflatoxin which is both a toxin and a carcinogen and which can potentially contaminate foods such as nuts. •Aspergillus fumigatus and Aspergillus clavatus can cause allergic disease. •Some Aspergillus species cause disease on grain crops,especially maize,and synthesize mycotoxins including aflatoxin. •Aspergillosis is the group of diseases caused by Aspergillus. The symptoms include fever, cough, chest pain or breathlessness. Usually, only patients with weakened immune systems or with other lung conditions are susceptible. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
- 10. 10 3. CRYPTOCOCCUS •Cryptococcus neoformans can cause a severe form of meningitis and meningo-encephalitis in patients with HIV infection and AIDS. The majority of Cryptococcus species live in the soil and do not cause disease in humans. • Cryptococcus neoformans is the major human and animal pathogen. Cryptococcus laurentii and Cryptococcus albidus have been known to occasionally cause moderate-to-severe disease in human patients with compromised immunity. •Cryptococcus gattii is endemic to tropical parts of the continent of Africa and Australia and can cause disease in non- immunocompromised people. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
- 13. 4. HISTOPLASMA Histoplasma capsulatum can cause histoplasmosis in humans, dogs and cats. Infection is usually due to inhaling contaminated air. 2. TYPES OF FUNGAL INFECTIONS 13 Mr.Ganesh D.Mote
- 14. 14 2. TYPES OF FUNGAL INFECTIONS HISTOPLASMA INFECTIONSMr.Ganesh D.Mote
- 15. 15 5. PNEUMOCYSTIS Pneumocystis jirovecii (or Pneumocystis carinii) can cause a form of pneumonia in people with weakened immune systems, such as premature children, the elderly, and AIDS patients. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
- 16. 16 2. TYPES OF FUNGAL INFECTIONS PNEUMOCYSTISMr.Ganesh D.Mote
- 17. 6. STACHYBOTRYS Stachybotrys chartarum or "black mold" can cause respiratory damage and severe headaches. It frequently occurs in houses in regions that are chronically damp. 2. TYPES OF FUNGAL INFECTIONS 17 Mr.Ganesh D.Mote
- 18. 18 7. MICROSPORUM Microsporum canis is a fungus that can cause tinea capitis in humans, and simple ringworm in pets. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
- 19. MICROSPORUM CANIS INFECTION 2. TYPES OF FUNGAL INFECTIONS 19 Mr.Ganesh D.Mote
- 20. 20 The fungus genus Trichophyto n rubrum is characterized by the development of both smooth-walled macro- and microconidia. Macroconidiaare mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick- walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 ÎĽm in size 8. TRICHOPHYTON 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
- 21. 2. TYPES OF FUNGAL INFECTIONS TRICHOPHYTON INFECTION 21
- 23. Chemical classification with structure Mr.Ganesh D.Mote23 1.Antifunal antibiotics a.Polyene antibiotics b.Other antifungal antibiotics griseofulvin
- 25. 25 3. CHEMICAL STRUCTURES AZOLE ANTIFUNGAL DRUGS Mr.Ganesh D.Mote
- 27. 27 6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS Con… POLYENES IMIDAZOLES TRIAZOLE ALLYLAMINES OTHER GLUCAN SYNTHASE INHIBITORS BIND TO ERGOSTEROL AND FORM PORES (CHANNELS) Mr.Ganesh D.Mote
- 28. 6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS ALLYLAMINES IMIDAZOLES TRIAZOLE POLYENES 28 GLUCAN SYNTHASE INHIBITORS
- 29. 29 6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS Mr.Ganesh D.Mote
- 30. FLUCYTOSINE IMIDAZOLES TRIAZOLES POLYENES CANDINS GRISEOFULVIN OTHERS 30 7. ANTI FUNGAL DRUGS MECHANISAM Mr.Ganesh D.Mote
- 31. 31 8.MECHANISM OF AMPHOTERICIN B Several amphotericin B molecules bind to ergosterol in the plasma membranes of sensitive fungal cells. There, they form pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antibiotic and the sterol. The pores disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death. Mr.Ganesh D.Mote
- 32. Flucytosine enters fungal cells via a cytosine-specific permease an enzyme not found in mammalian cells. Flucytosine is then converted by a series of steps to 5-fluorodeoxyuridine 5'- monophosphate. This false nucleotide inhibits thymidylate synthase, thus depriving the organism of thymidylic acid an essential DNA component. Note: [Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell. Thus, 5-FC and amphotericin B are synergistic.] 9.MECHANISM OF FLUCYTOSINE 32 Mr.Ganesh D.Mote
- 33. 10.MECHANISM OF KETOCONAZOLE Azoles are predominantly fungistatic. They inhibit C-14 α-demethylase (a cytochrome P450 enzyme), thus blocking the demethylation of lanosterol to ergosterol the principal sterol of fungal membranes. This inhibition disrupts membrane structure and function and, thereby, inhibits fungal cell growth. [Note:In addition to blocking fungal ergosterol synthesis, the drug also inhibits human gonadal and adrenal steroid synthesis, leading to decreased testosterone and cortisol production. In addition, ketoconazole inhibits cytochrome P450] 33 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D Mr.Ganesh D.Mote
- 34. Terbinafine inhibits fungal squalene epoxidase, thereby decreasing the synthesis of ergosterol . This plus the accumulation of toxic amounts of squalene result in the death of the fungal cell. 11.MECHANISM OF TERBINAFINE 34 Mr.Ganesh D.Mote
- 35. 35 It is only fungistatic, and it causes a number of significant drug interactions. Griseofulvin accumulates in newly synthesized, keratin-containing tissue, where it causes disruption of the mitotic spindle and inhibition of fungal mitosis . 12. MECHANISM OF GRISEOFULVIN Mr.Ganesh D.Mote
- 36. 36 13. SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS Mr.Ganesh D.Mote
- 37. 37 14. SOME ADVERSE REACTIONS OF AMPHOTERICIN B. Mr.Ganesh D.Mote
- 42. 42 Griseofulvin Flucytosine Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D Mr.Ganesh D.Mote
- 43. SAR OF AZOLE ANTIFUNGAL AGENTS 1. The basic structural requirement for members of the azole class is a weakly basic imidazole or 1,2,4-triazole ring (pKaof 6.5–6.8) bonded by a nitrogen–carbon linkage to the rest of the structure. 2. At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of molecular oxygen and prevent oxidation of steroidal substrates by the enzyme. 3. The most potent antifungal azoles possess two or three aromatic rings, at least one of which is halogen substituted (e.g., 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl), and other nonpolar functional groups. 4. Only 2, and/or 2,4 substitution yields effective azole compounds. 5. The halogen atom that yields the most potent compounds is fluorine, although functional groups such as sulfonic acids have been shown to do the same. 6. Substitution at other positions of the ring yields inactive compounds. 7. Presumably, the large nonpolar portion of these molecules mimics the nonpolar steroidal part of the substrate for lanosterol 14-demethylase, lanosterol, in shape and size. 8. The nonpolar functionality confers high lipophilicity to the antifungal azoles. 9. The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. 10.Fluconazole, which possesses two polar triazole moieties, is an exception, in that it is sufficiently water soluble to be injected intravenously as a solution of the free base. 43 Clotrimazole Fluconazole
- 44. Mechanism action of squaline epoxidase(allyl amines and lanoseterol 14 ά demethylase inhibitor(Azoles derivatives) Mr.Ganesh D.Mote44
- 45. Synthesis of Ketoconazole 45 Cl Cl C O CH2Br 2-bromo-1-(2,4-dichlorophenyl)ethanone CH2OH HC H2C OH OH propane-1,2,3-triol Cl Cl C CH2Br O O CH2OH (2-(bromomethyl)-2-(2,4- dichlorophenyl)-1,3-dioxolan-4- yl)methanol C O Cl Cl Cl C O O CH2COO C H2 N N Cl Cl C O O C H2 N N H2 C O SO2CH3 CH3SO3Cl
- 46. Mr.Ganesh D.Mote46 1-(3,4-dichlorophenyl)-2-(1H- imidazol-1-yl)ethanone Cl C O H2 C N Cl N Cl C H OH H2 C N Cl N 1-(3,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol NaBH4 Cl Cl H2 CBr 1-(bromomethyl)-2,4-dichlorobenzene Synthesis of Miconazole
- 47. Mr.Ganesh D.Mote47 2-Naphthol thiophosgene N-methyl 3-toludine O Cl S O-naphthalen-2-yl carbonochloridothioate O N S CH3 CH3 O-naphthalen-2-yl methyl(m-tolyl)carbamothioate Synthesis of Tolnaftate