Lecture 7. Antifungal Drugs Part 2 PDF

PHCM 413: Medicinal Chemistry II Lecture 7. Antifungal Drugs Part 2  Classification of Antifungal Drugs 1- Inhibitors of the cell membrane and its function A- Drugs affecting cell membrane function: Polyenes (Amphotericin B & Nystatin) B- Inhibitors of ergoste...

PHCM 413: Medicinal Chemistry II Lecture 7. Antifungal Drugs Part 2  Classification of Antifungal Drugs 1- Inhibitors of the cell membrane and its function A- Drugs affecting cell membrane function: Polyenes (Amphotericin B & Nystatin) B- Inhibitors of ergosterol synthesis 1-Azoles Imidazoles: Clotrimazole, Miconazole, Ketoconazole Triazoles: Itraconazole, Posaconazole, Fluconazole, Voriconazole 2- Allylamines: Terbinafine & Tolnaftate 3- Morpholines 2-Inhibitors of cell wall synthesis: Echinocandins (Caspofungin) 3-Inhibitors of RNA/DNA functions/mitosis inhibitors: Flucytosine – Griseofulvin Inhibitors of Ergosterol Synthesis Allylamines: inhibit squalene epoxidase Squalene epoxidase O Squalene 2,3-Oxidosqualene -demethylase CH2OH CHO HO HO HO HO Lanosterol 4,4-dimethylcholesta-8(9),14,24-trien-3-beta-ol Three-step demethylation of lanosterol, mediated by -demethylase Morpholines: inhibit delta(14)-sterol reductase delta(14)-sterol reductase H HO HO H H  Selected Triazole Antimycotics 1) Itraconazole Structurally related to ketoconazole. Ketoconazole 1,2,4-triazole 1,2,4-triazol-3-one 1 -1 2 4 Hydroxylation 3 (Active) More effective and better tolerated, orally active, broad-spectrum antifungal agent than ketoconazole (but much more expensive). 1) Itraconazole Advantages over ketoconazole: Not hepatotoxic, no anti-androgenic effects. Effective against Aspergillus infections. Longer half-life (20-30 h) than ketoconazole (6-9 h), active hydroxy- Cl metabolite -1 hydroxylation). Cl O N O N N N N O N N N HO O Hydroxy-itraconazole (active metabolite of itraconazole) Like ketoconazole, oral absorption requires acidic conditions. not used to treat meningitis and fungal CNS infections. Both Ketoconazole and itraconazole are potent CYP3A4 inhibitors Therefore, we have to decrease the conc. of co-administrated drugs that are CYP3A4 substrates, such as the hypnotic triazolam and the immunosuppressant cyclosporin.  2) Posaconazole Novel -1 hydroxyl metabolite. Cl ‫ن خلقه عنده هيدروكسي قروب ف‬F ‫مايحتاج هيدروكسليشن‬ ‫زم‬F ‫تراكينازول عكس‬F‫يروح ك سكند باس ميتابولزم اما ا‬ Cl ‫ مهمة‬، Z‫هيدروكسل‬ O N O N N N N O N N N O Itraconazole ‫يعني مقارنة مع الدواء اللي قبل نشوف‬ ‫ مو مهمه مره بس افهميها‬، ‫فات‬C‫خت‬F‫ا‬ phase II glucuronide conjugation Red parts in the structure indicate the differences from itraconazole Used to treat invasive infections by Candida, and Aspergillus species in immunosuppressed patients. Metabolized mainly by phase II glucuronide conjugation (not by CYP450) fewer drug interactions (advantage over ketoconazole and itraconazole). 3) Fluconazole F Two triazole rings + hydroxy group water soluble for oral and IV administration. Excellent oral bioavailability (90%) not affected F N by the presence of food or gastric pH. N N Long half-life (27-34 h). OH N N For the treatment of candidiasis and cryptococcosis. N Penetrates into CNS and CSF Drug of choice for treating cryptococcal meningitis. Topically against vaginal candidiasis. Little hepatic metabolism, excreted unchanged in the urine. ‫يناسب ا^رضى اللي عندهم مشاكل بالكبد‬ 4) Voriconazole ‫يجي مرسوم ونسوي له ميتابولزم‬ F F Fluconazole analog: one triazole replaced by fluorinated pyrimidine and has an additional methyl group. F N F N N N N Broader spectrum of activity than fluconazole. OH OH N N F N N N N Fluconazole Voriconazole Unlike fluconazole, it is active against Aspergillus and is more potent against Candida (a new standard in the treatment of invasive Aspergillosis). Good oral absorption and penetration of the blood-brain barrier. F Metabolism: Unlike fluconazole, extensive CYP450 N-oxidation interactions Methyl hydroxylation F N N N-oxidation OH N F N N methyl hydroxylation  Classification of Antifungal Drugs 1- Inhibitors of the cell membrane and its function A- Drugs affecting cell membrane function: Polyenes (Amphotericin B & Nystatin) B- Inhibitors of ergosterol synthesis 1-Azoles Imidazoles: Clotrimazole, Miconazole, Ketoconazole Triazoles: Itraconazole, Posaconazole, Fluconazole, Voriconazole 2- Allylamines: Terbinafine & Tolnaftate 3- Morpholines 2-Inhibitors of cell wall synthesis: Echinocandins (Caspofungin) 3-Inhibitors of RNA/DNA functions/mitosis inhibitors: Flucytosine – Griseofulvin  Inhibitors of Cell Wall Synthesis Echinocandins, also known as “penicillins of antifungal drugs, are expected to be nontoxic for humans as human cells do not have cell walls. Caspofungin: Semi-synthetic cyclic peptide with long lipophilic side chain long lipophilic side chain  Inhibitors of Cell Wall Synthesis Caspofungin Mode of action: inhibitor of 1,3- -glucan synthase.  Inhibitors of Cell Wall Synthesis Caspofungin Used in treating life-threatening systemic infections. Effective against Candida species resistant to other drugs. Effective against azole-resistant Aspergillus. Not effective against Cryptococcus neoformans. No oral bioavailability; IV administration. Limited hepatic metabolism No drug interactions.  Classification of Antifungal Drugs 1- Inhibitors of the cell membrane and its function A- Drugs affecting cell membrane function: Polyenes (Amphotericin B & Nystatin) B- Inhibitors of ergosterol synthesis 1-Azoles Imidazoles: Clotrimazole, Miconazole, Ketoconazole Triazoles: Itraconazole, Posaconazole, Fluconazole, Voriconazole 2- Allylamines: Terbinafine & Tolnaftate 3- Morpholines 2-Inhibitors of cell wall synthesis: Echinocandins (Caspofungin) 3-Inhibitors of RNA/DNA functions/mitosis inhibitors: Flucytosine – Griseofulvin  Inhibitors of RNA/DNA Functions (Mitosis Inhibitors) Flucytosine (5-fluorocytosine) Interferes with DNA/RNA F F O F NH2 O N NH HN N Fungal cytosine deaminase HN NH O O O O O O HO P OH Flucytosine OH 5-Fluorouracil (5-FU) 5-fluoro-2'-deoxyuridine 5'-monophosphate (Active metabolite) (5-FdUMP) 5-FU is a pyrimidine analog that can be misincorporated into RNA and DNA instead of uracil or thymine death O O O F HN HN HN O N O N O N H H H Uracil Thymine 5-FU  Inhibitors of RNA/DNA Functions (Mitosis Inhibitors) Flucytosine (5-fluorocytosine) Human cells do not contain cytosine deaminase. However, the enzyme or enzymes responsible for the deamination of flucytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to flucytosine, and this conversion may provide a mechanism through which flucytosine toxicity is manifested in humans. Orally active. Narrow spectrum of activity: indicated to treat severe systemic infections of Candida and Cryptococcus species.  Inhibitors of RNA/DNA Functions (Mitosis Inhibitors) Griseofulvin Antifungal antibiotic from Penicillium griseofulvum. ‫ﻛﻞ ﺷﻲ ﻣﮭﻢ ﻣﺎﻟﻲ ﺧﻠﻖ اﺣﺪد ﺷﻲ‬ It gets incorporated in newly synthesized keratin. O O O O O O Cl Mode of action: The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis (fungistatic).  Microtubule-dynamic polymers Microtubules are polymers of - and -tubulin protein heterodimers that associate longitudinally into protofilaments. Microtubules are involved in cell division, cell motility, 19 cell structure maintenance, and intracellular transport.