Antifungal agents.pptx by Dr. Rakam Gopi Krishna

In comparison with bacteria or viruses, fungi are more complex organisms.
They have ribosomes, cellular membrane components, and a nuclear membrane.
Therefore, antibacterial antibiotics are, as a rule, ineffective against pathogenic fungi.
Fungal infections (mycoses) occur less than bacterial or viral infections

1. Antifungal agents Dr. Rakam Gopi Krishna Associate Professor MLRIP HYD

2. Introduction In comparison with bacteria or viruses, fungi are more complex organisms. They have ribosomes, cellular membrane components, and a nuclear membrane. Therefore, antibacterial antibiotics are, as a rule, ineffective against pathogenic fungi. Fungal infections (mycoses) occur less than bacterial or viral infections

3. Fungi.. Fungi are small filamentous organisms. They live either as saprophytes or as parasites on plants and in human beings. They are classified as superficial and systemic infections. Superficial:- Hair, skin, nails and mucous membrane. Systemic:- entire body, deeper tissues and internal organs.

4. Fungal infections are usually more difficult to treat than bacterial infections, because fungal organisms grow slowly and fungal infections often occur in tissues that are poorly penetrated by antimicrobial agents (e.g., devitalized or avascular tissues). Therapy of fungal infections usually requires prolonged treatment.

5. I. Antif ungal s damaging permeability of the cell membrane Imidazoles: Clotrimazole, Ketoconazole, Miconazole Triazoles: Fluconazole, Itraconazole, Voriconazole A llylamine s : Terbinafine, Naftifine Thiocarbamates: Tolnaftate P olyene antibiotics: Amphotericin B, Nystatin II. Antifungals inhibiting chitin synthesis in the cell wall Caspofungin, Griseofulvin III. Antifungals inhibiting synthesis of nucleic acids Flucytosine

6. Various types of Drugs Antifungal drugs can be divided into Polyenes :- Amphotericin-B, Nystatin & Natamycin . Heterocyclic benzofuran :- Griseofulvin Imidazoles ( Triazoles ) :- Clotrimazole , Ketoconazole & Miconazole. Allylamines :- Naftifine & Terbinafine.

7. Few points on Drugs These compounds have broad spectrum of antifungal activity They possess fungicidal and fungistatic activity Antifungal agents act by various mechanisms

8. Azoles - Imidazoles & Triazoles Some imidazole derivatives are extremely beneficial for treating fungal infections. Clotrimazole Ketoconazole Miconazole Econazole Butaconazole Fluconazole

9. Azoles contn .. Azoles are synthetic antifungal agents. Azoles are 5-membered ring structures with nitrogen groups. Based on number of nitrogen atoms present in the ring, azoles are grouped as i ) Imidazoles – 2 Nitrogens ii) Triazoles - 3 Nitrogens Both have similar antifungal spectrum and mechanism of action.

10. Imidazole & 1,2,4-triazole

11. SAR- Imidazole & 1,2,4-triazole 1 2 3 4 5 1 2 3 4 5

12. Structure Activity Relationship Imidazole or triazole rings are essential for antifungal activity. Nitrogen present at 3 rd position in imidazole & 4 th position in triazole is termed as Amidine nitrogen. This nitrogen impairs the functioning ability of P-450 enzymes by binding to the heme portion of the enzymes. Substitution of halogen atom at 2 nd position or at both 2 nd & 4 th positions results in potent antifungal drugs. 1 1 2 2 3 3 4 4 5 5

13. SAR of Azoles contn .. Substitution of halogen atom apart from 2 nd & 4 th positions on the azole ring gives rise to compounds devoid of Antifungal activity . Substitution of both flourine and sulphonic acids at 2 nd and or 2,4 positions have yielded potent drugs.

14. Synthesis of Clotrimazole 2-chlorotriphenyl Methyl chloride imidazole triethylamine Clotrimazole 1 2 3 4 5 6

15. Triethylamine is commonly employed as a base in organic synthesis. It is employed as a base during the preparation of esters, amides and other compounds from acyl chlorides or chlorides. Such reactions lead to the production of hydrochloric acid which combines with triethyl amine to form the salt. i.e , triethyl amine hydrochloride commonly called as Triethyl ammonium chloride. This reaction removes the hydrogen chloride from the reaction mixture & proceed to completion of reaction.

16. Synthesis of clotrimazole Clotrimazole is synthesized by reacting 2-chlorotriphenyl methylchloride with imidazole In the presence of triethylamine . Synonym- Canesten , lotrimin MOA :- it inhibits the biosynthesis of ergosterin in cytoplasmic membrane of fungi.

17. Mechanism of action Lanosterol Demethylation Ergosterol Azoles 14- α -demethylase The cell membrane without ergosterol is defective and results in the leakage of various ions and other useful substances leading to death of the fungus.

18. MOA of Azoles Azoles control the fungal infections by different mechanisms. Azoles bind to cytochrome P-450 class enzyme, i.e., 14 α -demethylase . lanosterol on demethylation produces ergosterol , by 14 α -demethylase and is required in fungal cell-wall synthesis.

19. Mechanism of action of Azoles Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. Greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects.

20. Clotrimazole cont.. Uses :- It is used for candidiasis and vaginal infections. It is used for tinea infections. Available in lotion and cream It is extensively protein bound and hence is not considered optimally bioavailable

21. b). Triazoles . Fluconazole & Ketoconazole Itraconazole Voriconazole Voriconazole is under clinical trials. They damage the fungal cell membrane by inhibiting enzyme desmethylase . They are selective Resistant to degradation

22. glycerol 2,4-dichloro phenacyl bromide cis-(2,4dichlorophenyl)-2-bromoethyl-4-hydroxymethyl-1,3-dioxolane Methane sulfonyl chloride Mesylate 1-acetyl-4-(4-hydroxy phenyl) piperazine benzoyl chloride Imidazole Ketoconazole 1 2 3 4 5 1 2 3 4 5 6 2 4 Intermediate 2 3 4 5 4 3 2 5 1 6 6 Synthesis of ketoconazole - HBr ketalisation

23. Synthesis of ketoconazole Ketoconazole: is synthesized from 2,4-dichlorophenacyl bromide, the ketalization of which using glycerol gives cis-2-(2,4-dichlorophenyl)-2-bromoethyl-4-hydroxymethyl-1,3-dioxolane (35.2.1). Acylating the hydroxyl group of this compound with benzoyl chloride, and then alkylating the resulting compound with imidazole gives the derivative (35.2.2)

24. Synthesis of ketoconazole Next, alkaline hydrolysis removes the benzoyl group, and a reaction with methanesulfonyl chloride gives a mesylate (35.2.3). Finally, alkylating the resulting 1-acetyl-4-(4-hydroxyphenyl) piperazine gives ketoconazole (35.2.4).

25. ketoconazole Is the first imidazole used orally for systemic infections MOA :- Ketoconazole is known to inhibit cholesterol biosynthesis. It possess higher affinity towards mammalian cytochrome P-450 enzymes. Which causes toxic effects.

26. Mechanism of action of ketoconazole

27. Moa MOA:-it inhibits cytochrome P-450 dependent enzymes, blocking the synthesis of ergosterol. It possess fungicidal and fungistatic activity. Uses It has a broad spectrum of antifungal activity including many candida infections. Adverse effects :- Anorexia, nausea and vomiting.

28. New Antifungal drugs Voriconazole a new azole is presently in clinical trials in the United states It has potent activity against a broad variety of fungi Posaconazole is now in phase III clinical trials

29. Other drugs Tolnaftate Synonyms of the drug are Tinatox , Tinactin and Tonoftal Uses:- for dermatophyte infections