Antifungal agents.pptx

SAR and Mechanism Of Action of Antifungal agents

1. ANTIFUNGAL AGENTS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Medicinal Chemistry,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

2. ANTIFUNGAL AGENTS These are the drugs or agents which are useful in the treatment of fungal infections are known as antifungal agents. OVER VIEW OF FUNGAL Generally, the fungi have four main characteristics Fungi are Eukaryotic (They have a nucleus and mitochondria) They are Heterotrophs (They depends on other organisms for food) They are multicellular They cannot move on their own

3. Fungal Infection in Humans = Mycosis Major Types of Mycoses Superficial Cutaneous Subcutaneous Systemic Opportunistic Symptoms vary from cosmetic to life threatening

4. Types of fungal infections I. Mucocutaneous (superficial) infections: a. Dermatophytes: Cause infection of skin, hai r , and nails e.g. Tinea capitis (scalp), tinea cruris (groin), tinea pedis (foot), onychomycosis (nails).

5. b. Yeasts: Cause infections of moist skin and mucous membranes e.g. Candida albicans causing oral, pharyngeal, vaginal, & bladder infections 5

6. II. Systemic mycoses: are fungal infections affecting internal organs. It occurs in immunocompromized patients e.g. cryptococcosis, and aspergillosis (lung). 6

7. 1. Antifungal antibiotics Polyenes – Amphotericin B and Nystatin Other antifungal antibiotics – Griseofulvin 2. Azoles: - Imidazole’s - Ketoconazole, Clotrimazole, Miconazole. Triazoles - Fluconazole, Itraconazole, Voriconazole and Posaconazole 3. Allylamines – Tolnaftate, Terbinafine and Naftifine. 4. β – 3-Glucan synthase inhibitor – Capsofungin, Micafungin and Anidulafungin 5. Pyrimidine derivatives (Nucleosides) - Flucytosine 6. Fatty acids and carboxylic acids – Sodium caprylate, Triacetin, Undecylenic acid, Benzoic acid, salicylic acid and Propionic acid 7. Phenols and their derivatives – Resorcinol and clioquinol Based on chemical structure and mechanism of action they are classified in to different types

8. Mechanism of Action

9. Antifungals  can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physiochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis.

10. ANTIFUNGAL ANTIBIOTICS POLYENES: These compounds consist of macrolytic lactones with distinct hydrophilic, lipophilic region along with conjugated -ene system of double bonds hence they are called polyene antibiotics. Based on number of double bonds they are classified in to different types Tetraenes- Natamycin Penta enes – Filipin Hexaenes – Nystatin, Endomycin Heptaenes – Amphotericin B and Candicidin

11. Mechanism of Action: They have an affinity for sterols containing membranes, especially Ergosterol which is a primary sterol for of the membrane of fungi and polyenes bind firmly to it, thereby causing leakage of essential cell constituents and altering the membrane permeability, which results in to cell death. NYSTATIN Nystatin is an antifungal medication that fights infections caused by fungus. Nystatin when taken by mouth is used to treat yeast infections in the mouth or stomach. Oral nystatin is not absorbed into your bloodstream and will not treat fungal infections in other parts of the body or on the skin.

12. Common Side effects of Nystatin include: Diarrhea, Nausea, Stomach pain or upset, Vomiting, Contact dermatitis, Stevens-Johnson syndrome, Hypersensitivity reactions, Skin irritation or redness. USES: Nystatin, sold under the brand name Mycostatin among others, is an antifungal medication. It is used to treat Candida infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections. It may also be used to prevent candidiasis in those who are at high risk.

13. AMPHOTERICINE B USES: Amphotericin B injection is used to treat serious and potentially life-threatening fungal infections. Amphotericin B injection is in a class of medications called antifungals. It works by slowing the growth of fungi that cause infection. Common side effects may include: N ausea, vomiting, stomach pain, diarrhoea , upset stomach, loss of appetite, muscle or joint pain, headache, ringing in your ears, pain, bruising, or swelling where the medicine was injected, weight loss or flushing (warmth, redness, or tingly feeling).

14. GRISEOFULVIN (2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H-spiro[1-benzofuran-2,1'-cyclohexan]-2'-ene-3,4'-dione. Adverse Effects: The more common side effects of griseofulvin can include: Rash, numbness or tingling in your hands or feet, yeast infections in your mouth, stomach pain, diarrhea, heartburn, nausea, vomiting. USES: Griseofulvin is an antifungal medicine that is used to treat infections such as ringworm, athlete's foot, jock itch, and fungal infections of the scalp, fingernails, or toenails. Griseofulvin may also be used for purposes not listed in this medication guide.

15. AZOLES Mechanism of action Azoles inhibit fungal cytochrome P450 (14 α demethylase) necessary for ergosterol synthesis, a major component of fungal cell membrane. This will alter membrane permeability and disrupt its function. They are broad spectrum fungistatic against many dermatophytes and candida.

16. CLOTRMAZOLE Synthesis: USES: Clotrimazole is used to treat skin infections such as athlete's foot, jock itch, ringworm, and other fungal skin infections (candidiasis). Adverse Effects: Some side effects can be serious. If you experience any of the following symptoms, stop using clotrimazole and call your doctor immediately: rash. hives. stomach pain. fever. chills. nausea. vomiting. foul-smelling vaginal discharge.

17. KETOCONAZOLE ketoconazole should be used only when you cannot use other antifungal medications. Ketoconazole can cause serious harm to your liver that may result in liver transplant or cause death. 1-[4-(4-{[2-(2,4-Dichlorophényl)-2-(1H-imidazol-1-ylméthyl)-1,3-dioxolan-4-yl] méthoxy } phényl ) -1-pipérazinyl] éthanone Adverse Effects: Common side effects of Nizoral include: nausea, vomiting, stomach pain, itching or skin rash, headache, dizziness, breast swelling. USES: Ketoconazole is used to treat skin infections such as athlete's foot, jock itch, ringworm, and certain kinds of dandruff. This medication is also used to treat a skin condition known as pityriasis (tinea versicolor), a fungal infection that causes a lightening or darkening of the skin of the neck, chest, arms, or legs.

18. MICONAZOLE USES: Vaginal miconazole is used to treat vaginal yeast infections in adults and children 12 years of age and older. Miconazole is in a class of antifungal medications called imidazoles . It works by stopping the growth of fungi that cause infection. Adverse effects: Burning, stinging, swelling, irritation, redness, pimple-like bumps, tenderness, or flaking of the treated skin may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

19. ITRACONAZOLE USES: Itraconazole tablets and capsules are used to treat fungal infections of the toenails. Itraconazole oral solution (liquid) is used to treat yeast infections of the mouth and throat or of the esophagus (tube that connects the throat to the stomach). Itraconazole is in a class of antifungals called triazoles. Adverse Effects: Common side effects may include, headache, dizziness, drowsiness, tiredness, increased blood pressure, rash, itching, nausea, vomiting, stomach pain, diarrhea, constipation, swelling, abnormal liver function or blood tests, fever, muscle or joint pain, unusual or unpleasant taste in your mouth.

20. FLUCONAZOLE Adverse Effects: Headache, diarrhea, nausea or upset stomach, dizziness, stomach pain, vomiting, changes in the way food tastes, severe rash in people with lowered immunity. USES: Fluconazole is used to treat serious fungal or yeast infections, such as vaginal candidiasis, oropharyngeal candidiasis (thrush, oral thrush), esophageal candidiasis (candida esophagitis), other candida infections (including urinary tract infections, peritonitis [inflammation of the lining of abdomen or stomach]. 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl) propan-2-ol.

21. SAR OF AZOLE ANTIFUNGAL AGENTS 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. 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. 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.

22. SAR OF AZOLE ANTIFUNGAL AGENTS Only 2, and/or 2,4 substitution yields effective azole compounds. 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. Substitution at other positions of the ring yields inactive compounds. 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.

23. SAR OF AZOLE ANTIFUNGAL AGENTS The nonpolar functionality confers high lipophilicity to the antifungal azoles. The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. 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.

24. TOLNAFTATE Synthesis: Adverse Effects: Irritation of the treated skin may occur. If this effect persists or worsens, notify your doctor or pharmacist promptly. A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. Uses: Tolnaftate is used to treat skin infections such as athlete's foot, jock itch, and ringworm. It is an antifungal that works by preventing the growth of fungus.

25. Mechanism of Action: Although the exact  mechanism of action  is not entirely known, it is believed to inhibit squalene epoxidase, an important enzyme in the biosynthetic pathway of ergosterol (a key component of the fungal cell membrane) in a similar way to terbinafine.

26. CASPOFUNGIN Mechanism of Action: Caspofungin blocks the synthesis of β(1,3)-d-glucan of the fungal cell wall, by non-competitive inhibition of the enzyme β(1,3)-d-glucan synthase. β(1,3)-d-Glucan is an essential component of the cell wall of numerous fungal species. Adverse Effects: Nausea, vomiting, diarrhea, fever , flushing (warmth, redness, or tingly feeling of the skin), headache, irritation at the injection site, skin rash or itching. Uses: Caspofungin is an antifungal medicine that fights infections caused by fungus. Caspofungin is used to treat fungal infections of the stomach, lungs, esophagus , or other internal body areas.

27. FLUCYTOSINE 4-Amino-5-fluoro-2(1H)-pyrimidinone Adverse Effects: Nausea, vomiting, loss of appetite, diarrhea, headache, dizziness, numbness, tingling, or burning pain in your hands or feet, dry mouth or skin rash, Depression of bone marrow at high doses, hair loss. Uses: Flucytosine is used to treat serious fungal infections in the body. It belongs to a class of drugs known as antifungal drugs. It is often used with other medications. It works by slowing the growth of certain types of fungus.

28. Mechanism of Action: Flucytosine  enters the fungal cell via cytosine permease; thus,  flucytosine  is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism.