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Medicinal Chemistry of Antifungal Agents Dr. Afshin Fassihi Faculty of Pharmacy MUI Azar,1394 1 Introduction Long before Pasteur and Köch works on pathogenic bacteria Gruby and Schönlein have been studying a pathogenic fungi, Trichophyton schöenleinii (1839). The causative microorganism for thrush Candida albicans was discovered in the same year. But medical mycology was neglected under the shadow of medical bacteriology, maybe for the nonmalignancy of the fungal diseases. 2 Types of Fungal Infections (Mycoses) The term fungi is a general term that includes both yeasts and moulds. Fungal infections fall into two distinct categories: 1) Superficial Mycoses, Dermatophytoses. 2) Deep-Seated Mycoses, Systemic Mycoses. 3 Fungal Cell Structure and Targets Eukaryotes, like mammalian cells, with many similar biochemical structures: • DNA is organized into chromosomes within the nucleus • Distinct cytoplasmic organelles: endoplasmic reticulum, Golgi apparatus, mitochondria, and storage vacuoles. • Cell membrane This homology to mammalian cells also extends to biosynthetic pathways, where fungi share similar mechanisms for DNA replication and protein synthesis. 4 Fungal Cell Structure and Targets The two primary differences between fungi and higher eukaryotes have been exploited by medicinal chemists: The constitution of the cell membrane and The architecture of the cell wall. 5 Fungal Cell Membrane and Cell Wall 6 Mammalian Cell Membrane 7 Fungal Cell Membrane: Lipid bilayars form an unstable structure which cannot retain its shape and functions. Sterols lie within the lipid bilayer and act as stiffening agents. Sterols, account for approximately 25% of the weight of the cell membrane. The predominant sterol in mammalian cell membranes: cholesterol, The predominant sterol in fungal cell membranes: ergosterol. This difference is a target in selective antifungal design. 8 H3C CH3 CH3 H CH3 H H H3C H H3C HO CH3 CH3 CH3 H Cholesterol CH3 H H3C H HO Ergosterol 9 Drugs Affecting Ergosterol Biosynthesis 10 Drugs Affecting Ergosterol Biosynthesis Biosynthesis of Ergosterol in Fungi Ergosterol is synthesized from squalene, an ethylenic hydrocarbon through several steps. In this biosynthetic pathway there are four target enzymes for antifungal drug therapy: 1) 2) 3) 4) H3C Squalene epoxidase 14α-demethylase Δ14-reductase Δ7, Δ8-isomerase CH3 19 12 18 11 1 2 HO CH3 9 3 4 CH3 17 13 16 8 H 7 14 H CH3 H H3C 15 6 10 5 Ergosterol 11 12 Squalene Epoxidase Inhibitors E-Allylamines and Related Compounds Discovered by Random Screening. Effective only against nail and skin dermatophytes (narrow spectrum of activity). Decrease in fungal membrane ergosterol. Increase in squalene level which is toxic for the fungi: the main mechanism of antifungal activity. 13 Allylamine and … Mammalian cells have the same enzyme in the cholesterol biosynthesis pathway with less affinity toward this inhibitors. IC50 for squalene epoxidase in Candida albicans is 0.03μM and for rat liver enzymes is 77μM (Drug: Terbinafine). Some are oral antifungal agents. N N N A tertiary allyl amine Unusual substituted tertiary allyl amines 14 Naftifine: The first antifungal allylamine, against tinea (ringworm) CH3 N Naftifine CH3 CH3 N C C C CH3 Terbinafine: Stronger, against tinea and onychomycosis (ringworm of the nail). CH3 Terbinafine CH3 C CH3 CH3 Butenafine: Against Candida albicans in tolnaftate resistant cases. CH3 N Tolnaftate: Against dermatophytosis caused by: Tricophytone, Microsporum and Epidermophytone. In artificial nail preparations. Butenafine CH3 S N O CH3 Tolnaftate 15 14α-demethylase Inhibitors An enzyme belonging to CYP450 hemoproteins It is involved in mammalian cholesterol synthesis too, but it needs a higher concentration of drug to be inhibited. IC50 for C. albicans demethylase is 10-9 M and for human enzyme is 10-6 M (Drug: Clotrimazole) 16 Heme Structure 17 CH3H3C CH3 CH3 CH3 CH3 HO CH3 O N N Fe N N H3C 14 alpha-Demethylase Heme CH3H3C CH3 CH3 CH3 CH3 HO CH2OH H3C CH3H3C CH3 CH3 CH3 CH3 HO CH(OH)2 H3C CH3H3C CH3 CH3 CH3 CH3 HO C(OH)3 H3C CH3H3C CH3 CH3 CH3 CH3 HO H3C -HCO2H 18 Mechanism of 14α-Demethylase Inhibition with Azole Compounds O CH3 N N O Cl Cl N1 or N3 of azole antifungals is basic and bonds to iron atom in the heme of CYP450, where the activated oxygen is bonded normally. O O N N N N Fe N N The other parts of the drug bond to specific sites of the enzyme. Ketoconazole 19 Azole Antifungals Broad spectrum activity, superficial and deep-seated mycoses. The azole ring can be diazole or triazole. Diazole antifungals (Imidazole derivatives) Clotrimazole, Miconazole Econazole: In the treatment of tinea and candidiasis. Cl Cl Cl O O N N N N C N N Cl Cl Cl Cl Clotrimazole Miconazole Cl Econazole 20 Azole Antifungals Ketoconazole: Broad spectrum. Orally for systemic mycoses: systemic candidiasis, coccidiomycosis, thrush and blastomycosis. Inhibits the human demethylase too and causes an decrease in the concentration of testosterone and corticosterone in human. Inhibits other P450s in human so increases the plasma concentration of cyclosporin, phenytoin or terfenadine. Cl Cl Ketoconazole O O N N O O N N C CH3 21 Azole Antifungals Triazole antifungals Fluconazole Voriconazole OH CH3 OH N N N N N F F Fluconazole F N N N CH3 N N F N F Voriconazole 22 Azole Antifungals Cl Itraconazole Cl O O N N O O N N N N N N F Posaconazole F O N O N N N O N N N N OH 23 SAR of Azole Antifungals 1. A basic imidazole or 1,2,4-triazole is essential for antifungal activity, N3 of imidazole and N1 of triazole binds to P450 iron. 2. The most active ones have two or three aromatic rings, at least one of them is substituted with halogens. 3. These substitutions are 2,4-dichloro or 2,4-difluoro. 4. The most active azoles have flour in the structure. 5. The big non-polar part resembles the steroid molecule in binding to the enzyme. 24 Δ14-reductase Inhibitors Amorolfine the only morpholino compound is such an inhibitor. In the treatment of dermatophytosis. H3C CH3 O N C C2H5 CH3 H3C Amorolfine 25 Δ7, Δ8-isomerase Inhibitors Amorolfine inhibits Δ7, Δ8-isomerase too. H3C CH3 O N C C2H5 CH3 H3C Amorolfine 26 Polyene Membrane disrupters Macrocyclic lactones with: a) hydrophilic parts; a number of hydroxyl groups on the ring and a desoxy amino hexose (mycosamine). b) hydrophobic ring with a number of double bonds. 27 Polyene Membrane disrupters They belong to two different groups: a) With a 26 member ring: Natamycin b) With a 38 member ring: Amphotericin B and Nystatin Amphotericin B Natamycin 28 Polyene Membrane disrupters Locally used in the treatment of dermal and GI infections caused by Candida albicans. Treatment of deep-seated mycoses caused by: Candida, Aspergillus, Cefalosporium, Penicillinum and Fusarium spp. 29 Mechanism of Antifungal Activity of Polyenes Act by binding to ergosterol in the fungal cell membrane. Hydrogen bonding between hydroxyl, carboxyl and amino groups of the drug and membrane makes the channel stable. Attach with higher affinity to ergosterol containing membranes than cholesterol containing ones. This forms pores in the membrane and increases its permeability eventually leading to cell death. 30 Mechanism of Antifungal Activity of Amphotericin B 31 Toxicities of Polyenes Stimulation of the host immune cells by amphotericin B: release of inflammatory cytokines by circulating monocytes resulting in: fever, chills, rigor, nausea, vomiting, myalgias, arthralgias, and headache during intravenous infusions. At higher concentrations, amphotericin B binds to cholesterol in mammalian cell membranes leading to various organ toxicities, most importantly nephrotoxicity. 32 Fungal Cell Wall: It is critical for cell viability and pathogenicity: A protective shell and provides cell morphology, A critical site for exchange and filtration of ions and proteins, A place for metabolism and catabolism of complex nutrients. Because mammalian cells lack a cell wall, it represents an ideal and specific target for antifungal therapy. 33 It is composed of a complex network of proteins and polycarbohydrates that varies in composition depending on the fungal species. Disruption of this protein/carbohydrate matrix results in a structurally-defective cell wall, rendering the fungal cell sensitive to osmotic lysis. 34 Agents Acting on The Cell Wall: Glucan synthesis inhibitors They do this by inhibiting the enzyme 1,3-beta glucan synthase. It results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress. β-1,3 Glucan 35 36 Echinocandins Herbal peptide discovered in 1970’s. Contains a large cyclic peptide attached to a long chain fatty acid. 37 Pneumocandin (Caspofungin) Herbal peptide FDA approved which is used to treat aspergillosis. 38 Nucleoside Antifungals Fungal and mammalian cells share remarkable homology in DNA replication and RNA translation: DNA and protein synthesis are difficult targets for developing selective antifungal agents The only class of agents in clinical use that target DNA/RNA synthesis: Antimetabolites This class has only one example: Flucytosine or 5-fluorocytosine (5-FC). 39 Antimetabolites Flucytosine NH2 F NH 5-FC N H O Cytosine Permease Cytosine Deaminase O F NH N H O 5-FU 40 Mechanism of Antifungal Action O F NH N H O 5-FU O O F F NH N O NH O N O O - O P OH2C - O P O P O P O- 5-FdUTP O O P O- O O P OH2C OH - OH O O O O O- Blocks DNA synthesis by inhibiting thymidylate synthetase O- O- O OH 5-FUTP Incorporates into RNA, synthesis of non-sense proteins 41 Mechanism of Adverse Effects of 5-FC Developed in the 1950's as a potential antineoplastic agent but, it was ineffective since mammalian cells do not have cytosine deaminase but, Flucytosine can be converted to 5-FU by bacteria residing in the gastrointenstinal tract. The most common adverse effects seen with flucytosine are similar to 5-FU chemotherapy (diarrhea, nausea and vomiting, bone marrow suppression) but at reduced intensity. 42 Miscellaneous Agents: Griseofulvin Isolated from Penicillium griseofulvum. Griseofulvin inhibits fungal cell mitosis by disrupting mitotic spindle formation-a critical step in cellular division. It is used orally for superficial mycoses, enters in the structure of the precursors of keratin. 43 • • • • • • • • • Tinea is a general term used to describe skin mycoses. The term ringworm is even less precise, but is usually considered a synonym. Onychomycosis (also known as "dermatophytic onychomycosis" "ringworm of the nail" and "tinea unguium") means fungal infection of the nail. It is the most common disease of the nails and constitutes about a half of all nail abnormalities. Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or C. posadasii. The disease is usually mild, with flu-like symptoms and rashes. Blastomycosis (also known as "North American blastomycosis," "Blastomycetic dermatitis," and "Gilchrist's disease") is a fungal infection caused by the organism Blastomyces dermatitidis. can present in one of the following ways: a flu-like illness with fever, chills, myalgia, headache, and a nonproductive cough which resolves within days. an acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain. skin lesions, usually asymptomatic, appear as ulcerated lesions with small pustules at the margins bone lytic lesions can cause bone or joint pain. prostatitis may be asymptomatic or may cause pain on urinating. laryngeal involvement causes hoarseness. 44