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Medicinal Chemistry of Antifungal Agents PowerPoint Presentation

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Description : Check out this medical titled "Medicinal Chemistry of Antifungal Agents” by Dr. R.SIVAKUMAR, M.PHARM,PhD.

This medical is about antifungal agents which are drugs that are used to treat fungal infections. Fungal infections can affect different parts of the body, including the skin, nails, hair, and internal organs, and can range from mild to life-threatening. The medicinal chemistry of antifungal agents involves the design, synthesis, and evaluation of compounds that target specific components of fungal cells.

Fungal cells are eukaryotic and have many similarities to human cells, making it challenging to develop antifungal agents that are selective and effective while minimizing toxicity to human cells. The main targets for antifungal agents are the fungal cell wall, cell membrane, and various enzymes involved in fungal metabolism.

Tags : Medicinal Chemistry of Antifungal Agents, antifungal agents, fungal infections, Infectious Disease, Infectious Disease

Published on : Jun 01, 2023 | Views : 1101 | Downloads : 0

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Medicinal Chemistry of Antifungal Agents Dr. R.SIVAKUMAR M.PHARM,Ph.D Professor&HOD Department of Pharmaceutical Chemistry
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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. Gruby applied the causative fungi for favus on a kid’s scalp to induce the infection successfully. But medical mycology was neglected under the shadow of medical bacteriology, maybe for the non-malignancy of the fungal diseases.
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Types of Fungal Infections (Mycoses) The term fungi is a general term that includes both yeasts and molds. Fungal infections fall into two distinct categories: Superficial Mycoses, Dermatophytoses. Deep-Seated Mycoses, Systemic Mycoses.
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Superficial Mycoses Contagious skin infections that are limited to the epidermal region. Most common fungal infections in the form of skin, hair and nail lesions. Caused by a relatively homogenous group of fungi, dermatophytoses, specialized saprophytic molds that unusually digest keratin of the skin.
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Systemic Mycoses Non-contagious infection that invade the skin, lungs and lymphatic tissue. In the case of neonates who have acquired the etiological agent of candidiasis from their mother it is contagious. There are different systemic mycosis, e.g., histoplasmosis, blastomycosis, sporotrichosis and coccidiomycosis. The causative agents are free-living saprophytes.
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Fungal Cell Structure and Targets Like mammalian cells, fungi are eukaryotes with many similar biochemical structures, especially cell membranes to mamalian cells. DNA is organized into chromosomes within the cell nucleus and have distinct cytoplasmic organelles including endoplasmic reticulum, Golgi apparatus, mitochondria, and storage vacuoles. This homology to mammalian cells also extends to biosynthetic pathways, where fungi share similar mechanisms for DNA replication and protein synthesis.
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The similarity of fungal and mammalian cells creates a number of problems for designing drugs that are selectively toxic to fungal cells but not the human host.
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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. Whereas mammalian cell membranes contain primarily cholesterol, ergosterol is the predominant sterol in many pathogenic fungi. This difference in sterol content has been exploited as the target of selective antifungal drug action.
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Fungal Cell Wall: The fungal cell wall is critical for cell viability and pathogenicity. Beyond serving as a protective shell and providing cell morphology, the fungal cell wall is a critical site for exchange and filtration of ions and proteins, as well as metabolism and catabolism of complex nutrients. Because mammalian cells lack a cell wall, it also represents an ideal and specific target for antifungal therapy.
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Structurally, the fungal cell wall 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.
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Agents Acting on The Cell Wall:Glucan synthesis inhibitors Because of lacking the cell wall, interruption in the fungal cell wall biosynthesis would be safe for the mammalian host. They do this by inhibiting the enzyme 1,3-beta glucan synthase. Inhibition of this enzyme results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress.
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Echinocandin and Pneumocandin were herbal compounds discovered in 1970’s able to block cell wall synthesis. They are peptide compounds with a long lypophil chain that inhibit β-1,3-d-glucan synthase, an enzyme resposible for the synthesis of β-glucan polymers. A recently FDA approved drug of this category is Caspofungin (pneumocandin) which is used to treat aspergillosis.
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Echinocandin
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Pneumocandin(Caspofungin)
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Drugs Affecting Ergosterol Biosynthesis Biosynthesis of Ergosterol in Fungi Ergosterol is synthesized from squalene, an ethylenic hydrocarbon through several steps, with lanosterol as an steroid intermediate. In this biosynthetic pathway there are four target enzymes for antifungal drug therapy: Squalene epoxidase 14α-demethylase Δ14-reductase Δ7, Δ8-isomerase
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Squalene Epoxidase Inhibitors Allylamines and Related Compounds They were discovered by Random Screening in order to find antifungal agents. They are only effective against nail and skin dermatophytes (narrow spectrum of activity). They cause a decrease in fungal membrane ergosterol and an increase in squalene level which is toxic for the fungi.
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Allylamine and … Mammalian cells have the same enzyme in the cholesterol biosynthesis pathway with less affinity toward this inhibitors. Ki for squalene epoxidase in Candida albicans is 0.03μM and for rat liver enzymes is 77μM (Drug: Terbinafine). Some are oral antifungal agents.
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Naftifine: The first antifungal allylamine, against tinea. Terbinafine: Stronger, against tinea and onychomycosis (oral). Butenafine: Against Candida albicans in tolnaftate resistant cases. Tolnaftate: Against dermatophytosis caused by tricophytone, mycrosporum and epidermophytone. In artificial nail preparations.
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14α-demethylase Inhibitors In superficial and deep-seated mycoses. High bioavailability after oral absorption and broad spectrum of antifungal activity. 14α-demethylase is an enzyme in mammalian cholesterol synthesis too, but it needs a more concentration of drug to be inhibited. IC50 for C.albicans demethylase is 10-9 and for human enzyme is 10-6 .
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Mechanism of 14α-Demethylase Inhibition with Azole Compounds N3 of azole antifungals is basic and bonds to iron atom in the heme of CYP450, where the activated oxygen is bonded normally. The other parts of the drug bonds to specific sites of the enzyme.
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Toxic Effect of Azole on Fungal Cell Membrane
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Azole Antifungals Clotrimazole: In the treatment of tinea and candidiasis. Butoconazole: In the treatment of vaginal candidiasis.
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Azole Antifungals Econazole: In the treatment of tinea and candidiasis. Miconazole: Against severe systemic mycosis: coccidiomycosis (parentheral). Very broad-spectrum.
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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.
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SAR of Azole Antifungals A basic imidazole or 1,2,4-triazole with a pKa of 6.5-6.8 is essential for antifungal activity. N3 of imidazole and N4 of imidazole of triazole binds to P450 iron. The most active ones have two or three aromatic rings, at least one of them is substituted with halogens or other nonpolar groups (2,4-dichlorophenyl 1,4-dichlorophenyl, or 2,4-difluorophenyl). The most active azoles have fluore in the structure. Ring substitution at other positions makes the azole inactive. The big nonpolar part resembles the steroid molecule in binding to the enzyme.
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Δ14-reductase Inhibitors Amorolfine the only morpholino compound is such an inhibitor. In the treatment of dermatophytosis.
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Δ7, Δ8-isomerase Inhibitors Amorolfine inhibits Δ7, Δ8-isomerase too.
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Polyene Membrane disrupters Macrocyclic lactones with: hydrophilic parts; a number of hydroxyl groups on the ring and a deoxy amino hexose (mycosamine). hydrophobic ring with a number of double bonds. They belong to two different groups: With a 26 member ring: Natamycin With a 38 member ring: Amphotericin B and Nystatin They were introduced to cure the deep-seated mycoses.
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Mechanism of Antifungal Activity of Polyenes Polyene antifungals act by binding to ergosterol in the fungal cell membrane. This binding results in the membrane formation of pores that increase permeability to proteins and monovalent especially K+ and divalent cations, eventually leading to cell death. Polyenes attach with higher affinity to ergosterol containing membranes than cholesterole containing ones.
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Toxicities of Polyenes Amphotericin B may also induce oxidative damage in fungal cells and has been reported to stimulate of host immune cells. Stimulation of the host immune cells by amphotericin B causes 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.
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Amphotericin B
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Amphotericin B forms a transmembrane channel after interaction with mmembrane steroles. Hydrogen bonding between hydroxyl, carboxyl and amino groups of the drug and membrane makes the channel stable. It is used in lethal fungal infections such as coccidimycosis and histoplasmosis.
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Mechanism of Antifungal Activity of Amphotericin B
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Possible molecular assemblage formed in biomembrane by amphotericn B, sterol and phospholipid
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The effect of Amphotericin B on the Fungal Cell Membrane
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The effect of Amphotericin B on the Fungal Cell Membrane
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Nystatain
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Nystatain The first polyene entered the clinic without systemic absorption. The macrocyclic ring contains 38 atoms. Locally used in the treatment of dermal and GI infections caused by Candida albicans.
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Schematic representation of the main stages of nystatin interaction with a model system of membranes. After adsorption to the membrane interface (top), the antibiotics self-associate in a pore structure (bottom), when the surface concentration is higher than a critical value. The structures formed in the biological membranes are most probably mixed antibiotic-sterol aggregates.
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Natamycin It has a macrocyclic ring with 26 atoms. It is used in the treatment of fungal infections caused by candida, aspergilus, cefalosporium, penicillinum and fusarium spp.
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Nucleoside Antifungals DNA and protein synthesis have historically been difficult targets for the development of selectively-toxic antifungal therapy, as fungal and mammalian cells share remarkable homology in DNA replication and RNA translation. However, advances in molecular biology and functional genomics are beginning to highlight important differences between mammalian and fungal cells that could be exploited for the development of new antifungal therapies. For the time being, only one class of agents in clinical use targets DNA/RNA synthesis: Antimetabolites
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Antimetabolites This class has only one example, flucytosine or 5-fluorocytosine (5-FC). Flucytosine was originally developed in the 1950's as a potential antineoplastic agent. Although ineffective against tumors it was later found to have antifungal activity. This small molecule is transported into susceptible fungal cells by a specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil (5-FU)- a pyrimidine anti-metabolite used as chemotherapy for many types of colorectal cancer
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Mechanism of Antifungal Action 5-FU is phosphorylated and incorporated into RNA where it causes miscoding and halts protein synthesis. Additionally, phosphorylated 5-FU is converted to its deoxynucleoside, which inhibits DNA synthesis by blocking the functions of a key enzyme in DNA replication- thymidylate synthetase.
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Mechanism of Adverse Effects of 5-FC Flucytosine can be converted to 5-FU by bacteria residing in the gastrointenstinal tract. Not surprisingly, 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.
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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. It doesn’t have local activity.
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Miscellaneous Agents: Fatty Acids Sebum, the naturally occurring fatty acid on the human skin is a natural antifungal agent and a part of the immune system. Fatty acids or their salts have antifungal activity: Sodium or zinc caprylate. Undecylenic acid.