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Lawrence A. Adutwum
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This document is a presentation on antifungal agents. It covers topics such as the characteristics of fungi, types of fungal infections, targets of antifungal agents, and some antifungal drugs.
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Antifungal, Antiviral and Antineoplastic Agents PHMD 312: Medicinal Chemistry of Infectious Disease Agents Lawrence A. Adutwum email: [email protected]/[email protected] Office: Room 18 Antifungal Agents Character...
Antifungal, Antiviral and Antineoplastic Agents PHMD 312: Medicinal Chemistry of Infectious Disease Agents Lawrence A. Adutwum email: [email protected]/[email protected] Office: Room 18 Antifungal Agents Characteristics of Fungi Properties of fungal agents. Types of fungal infections. Targets of antifungal agents. Some antifungal drugs. 2 What are Fungi Organisms from the fungus kingdom which includes: yeasts, moulds, rusts and mushrooms Largely useful and are involved in biodegradation. Fungal infections occurs when these organisms invades epithelial tissues. Introduction through wounds, lungs/nasal pathways leads to infections. White Fungus Mold Mushrooom 3 Types of Fungal Infections 1. Dermatophytic infection They require keratin for growth!! Superficial infections of the skin caused by dermatophytes in the genus Microsporum, Trichophyton and Epidermophyton. Infection Causative Organism Tinea corporis (ringworm) M. canis, T. mentagrophytes Tinea pedis (athlete’s foot) T. rubrum, Tinea cruis (jock itch) T. mentagrophytes, Tinea unguium (nails) E. floccosum Tinea capis (scalp) M. canis, T. tonsurans Tinea barbae (beard/hair) T. rubrum, T. mentagrophytes 4 Types of Fungal Infections 2. Systemic infections Caused by inhalation of spores leading to fungal pneumonia. It is not transmissible and can occur in healthy individuals. These are more common in the Americas (geographically confined) Infection Causative Organism Coccidioidomycosis Cocidioides immitis Histoplasmosis Histoplasma capsulatum Brazilian Paracoccidioides brasiliensis Blastomycosis Blastomycosis Blastomyces dermatitidis 5 Types of Fungal Infections 3. Opportunistic infections Causes life threatening infections in immunocompromised subjects, HIV patient, blood diseases, cancers, diabetics. Infection Causative Organism Candidiasis, Thrush, Candida albicans (GI tract and vagina) Vulvo-vaginitis Cryptococcal meningitis Cryptococus neoformans (Lungs, CNS) Aspergillosis Aspergillus sp. (Lungs, brain, sinuses, etc) Mucormycosis Murcor sp. (Sinuses, eyes, blood and brain) Pneuomocystis carinii Pneumocystis carinii (Lungs – in HIV patients) pneumonia 6 Targets of Antifungal Agents Fungal cells are complex are similar to eukaryotic cells. Share several similarities with other eukaryotes. The cell wall has unique organelles that fulfil the criteria for selective toxicity. Differs greatly for bacterial cell wall and hence not affected by cell wall inhibitors like β -lactams and Vancomycin. Even though different species have different arrangement of cell wall components, their composition is very similar. 7 Targets of Antifungal Agents Three (3) main mechanisms of antifungal agents Inhibition of cell wall formation Cell Membrane Disruption Inhibition of Cell Division 8 Targets of Antifungal Agents Inhibition of cell wall formation Cell Membrane Disruption 9 Inhibition of cell wall formation Interference with fungal cell wall biosynthesis has not been as successful and effective as penicillin and cephalosporins against bacteria. Many chemicals have been discovered that interfere with various steps in fungal cell wall synthesis with excellent antifungal activity in vitro. Development of these agents into useful drugs has proven very difficult. Many of these agents are developed to target β- glucan synthesis. 10 Cell Membrane Disruption Antifungal agents that disrupt the cell membrane do so by targeting ergosterol, either by binding to the sterol, forming pores and causing the membrane to become leaky (as with polyene antifungals), or inhibiting ergosterol biosynthesis (as seen with azole antifungal agents). Ergosterol is like mammalian cholesterol, thus agents binding ergosterol may have a cytotoxic effect in the host tissue. Ergosterol has two conjugated double bonds that are lacking in mammalian sterols. Cholesterol Ergosterol 11 Synthesis of cholesterol 12 Inhibition of Cell Division Targeting the microtubule effects in forming the mitotic spindle Late Mitotic Phase Inhibiting DNA transcription. 13 Types of Antifungal Agents Polyenes Amphotericin B, Nystatin, Natamycin Azoles and Triazoles Miconazole, Clotrimazole, Ketoconazole, Itraconazole, Fluconazole, Voriconazole,, Econazole, Oxiconazole, Sulconazole, Tioconazole, Terconazole, Pasaconazole, Butoconazole Allylamines (Ergosterol biosynthesis inhibitors): Terbinafine, Tolnaftate Cell membrane stability disruptors: Ciclopirox Inhibitors of cell division: Flucytosine, Griseofulvin Cell wall inhibitors/Echinocandins Caspofungin, Anidulafungin, Micafungin, Undecylenic acid, 14 Polyene Antifungal Agents AKA Cell Membrane Disruptors They were originally extracted from Streptomyces nodosus Cyclic molecules Considered to be very toxic!!! Amphotericin B, Nystatin, Natamycin Mepartricin (Currently used for Pelvic Pain Syndrome and Benign Prostatic Hyperplasia 15 Mechanism of Action of Polyenes Bind to ERGOSTEROL in the cell membrane, creating pores/tunnels making it leaky and cell death 16 Amphotericin B Yellow powder which is water insoluble at physiological pH. Soluble at pH ≤ 2 and pH ≥11 Weak association with bile sales improves solubility. Oral absorption is poor and must be given IV. Used in life-threatening severe systemic infections. 17 Amphotericin B Binds with sterols (ergosterol) and disrupts cell membrane by creating tunnels/pores. Rapid movement of monovalent ions, K+, Na+, H+, Cl- leading to cell death. Combination with azole is never synergistic, however combination with 5FC gives is synergistic. Total synthesis/Biosynthesis of Amphotericin B/polyketide can be found Carmel Marie McNamara 1997 thesis from University of Leicester. 18 Amphotericin B – Side effects Must be reserved only for severe infections. Non selective action on cholesterol in mammalian cell membrane leads to toxicities. Headache, fever, chills, anorexia, vomiting, muscle and joint pain. Severe renal toxicities linked to interaction with cholesterol. Early intolerance reaction, thrombophlebitis Nephrotoxicity, hematotoxic effects 19 Amphotericin B – Side effects Renal insufficiency (Nephrotoxicity) Hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia Serum creatinine and electrolyte levels must be monitored. Must be avoided in patience with Kidney disease. The liposomal preparation of Amphotericin B reduces the risk of nephrotoxicity. 20 Nystatin Nystatin was originally isolated from Streptomyces noursei in 1951. First polyene to be used. Binds to ergosterol in fungal membrane causing membrane to become leaky. 21 Nystatin Available in oral tablets, powder for suspension, vaginal tablets, pastilles, for local therapy only (not absorbed). Nystatin will treat gut candidiasis, and is used in a "swish and swallow" routine for oral candidiasis. No significant adverse effects with these uses, however itching, irritation and burning may occur. Rarely nystatin can cause diarrhea and nausea 22 Polyenes - Natamycin Natamycin was first isolated from cultures of Streptomyces natalensis. Structures consists of 26-membered lactone instead of the 38 for Nystatin and Amphotericin B. 23 Polyenes - Natamycin Like other polyene antifungal agents it binds to ergosterol in fungal membrane causing membrane to become leaky. The 26-membered polyenes cause both K leakage and cell lysis at same concentration Inhibits amino acid and glucose transport proteins across cell membrane. 24 Polyenes - Natamycin Natamycin is supplied as a 5% ophthalmic suspension intended for the treatment of fungal conjunctivitis, blepharitis and keratitis. Eye irritation, redness and swelling not present prior to use. 25 Synthesis of cholesterol 26 Allylamine and Thiocarbamate Terbinafine (allylamine) and Tolnaftate(thiocarbamate) Have a much more limited spectrum of activity than the azoles and triazoles. They are very effective against dermatophytes hence effective for fungal infection of skin and nails eg. athlete's foot, jock itch, and ringworm These antifungal agents are reversible, noncompetitive inhibitors of the first step in ergosterol biosynthesis, the conversion of squalene to squalene-2,3- epoxide by squalene epoxidase. The buildup of squalene in the cell membrane is toxic to the cell, causing pH imbalances and malfunction of membrane bound proteins. 27 Allylamine - Terbinafine Terbinafine Terbinafine is synthetic, highly lipophilic Oral and topical (cream) formulations Used to treat superficial and systemic mycosis Adverse reactions to terbinafine are in general transient and mild. Drug interactions: warfarin, antidepressant drugs, beta- blockers, proton pump inhibitors and drugs that suppress the immune system. 28 Thiocarbamate - Tolnaftate Tolnaftate The exact mechanism unknown; however, it has been reported to distort the hyphae and to stunt mycelial growth in susceptible organisms. Inhibition of squalene epoxidation has also been reported Effective against Tinea pedis (athlete's foot) 29 Synthesis of cholesterol 30 Azole Derivatives A chemical pentacyclic structure with 2 nitrogen atoms Water insoluble except fluconazole Preferentially inhibit cytochrome P450 enzymes Fungistatic, Modify cytochrome P450 enzyme. First generations Imidazoles. Clotrimazole (1969) Miconazole (1968) Clotrimazole requires high doses – poorly tolerated 31 Rehash Phase I metabolism – CYP 450 CYP is a host of enzymes that use iron to oxidize things. CYP disposes harmful substances by making them water-soluble. CYP is vital to the formation of cholesterol & steroids. Azole antifungal agents interfere with cytochrome P450 32 Ketoconazole Orally well absorbed imidazole of second generation Ketoconazole is the only imidazole for systemic use CSF penetration is very weak Hepatotoxicity restricts its use Also interacts with other molecules (2R,4S)-(+)-ketoconazole Restricted systemic use Topical products available (2S,4R)-(−)-ketoconazole 33 Third Generation They are mostly triazoles; contains three nitrogen atoms in a ring Fluconazole, Itraconazole, Voriconazole, Pasaconazole, Revuconazole. Satisfactory tolerability and hence used systemically A broad spectrum antifungal agent Rapid absorption after oral administration Distributes in tissues and body fluids Metabolized in the liver Hepatotoxicity, gastrointestinal and endocrine toxicity Skin rash, pruritis and other hypersensitivity 34 Fluconazole, Itraconazole, Vorionazole Fluconazole has been extensively used for yeast infections. Useful for systemic infections Readily and completely absorbed by gastrointestinal tract. Distributed equally in different organs and tissue. Candida krusei Intrinsically resistant to fluconazole. Itraconazole is used to treat aspergillus infections. Entirely metabolized in the liver. Eliminated in the feces and urine. (2R,4S)-(+)-itraconazole Fluconazole (2S,4R)-(−)-itraconazole Voriconazole 35 Clinical Indications of Azoles/Triazoles Miconazole has poor tolerability given by intravenous Ketoconazole used for endemic & superficial mycosis Fluconazole useful for C. albicans and Cryptococcus neoformans Voriconazole & Posaconazole have similar spectrum as other azole Itraconazole is used to treat bronchopulmonary aspergillosis Adverse effects: gastrointestinal, hypersensitivity & hepatotoxicity 36 Echinocandins They semisynthetic, synthesized from Glarea lozyensis Noncompetitively inhibition of β-1,3-D-glucan synthase enzyme Echinocandin B Caspofungin Micafungin Anidulafungin 37 Echinocandins Caspofungin Whitish powder, water & methanol soluble, fungicidal Fungicidal against, Aspergilli, Candida and P. carinii No cross resistance amongst strains resistant to Amphotericin B or Azoles/Triazole No activity against Cryptococcus neoformans, Fusarium & Rhizopus Effective against Pneumocystis carinii Micafungin and Anidulafungin – are under investigation 38 Cell wall synthesis inhibitors – under development β-1,3 glucan synthetase inhibitors: Papulacandins – glycolipid antifungal produced by Papularia sp. Loss of β-glucan results in weakening of the cell wall, thus internal pressures can cause the cells to lyse Chitin Synthase inhibitors: Polyoxins and Nikkomycins– nucleoside peptides. Chitin is also a major component to the cell wall and its loss will also weaken the cell walls. C Mannan binding antifungals: Pradimicins and Benanomicins. C-mannan is a cell wall glycoprotein that combats the host 39