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Antifungal agents
1.
© Ramaiah University
ofApplied Sciences 1 FacultyofPharmacy Anti-fungal antibiotics Preparedby:- Jatin Isher & Vishal Singh (B.pharm 3rd year) Global Group of InstitutesAmritsar Medicinal Chemistry-III
2.
© Ramaiah University
ofApplied Sciences 2 FacultyofPharmacy
3.
© Ramaiah University
ofApplied Sciences 3 FacultyofPharmacy Antifungal antibiotics • Important group • Two classes- polyenes and griseofulvin • Polyenes- complex antifungal antibiotics isolated from soil bacteria of the genus Streptomyces • Contain a system of conjugated double bonds in macrocyclic lactone rings • Different from erythromycin type structures(macrolides) • Larger and contain the conjugated -ene system of double bonds- called polyenes • Clinically useful polyenes- two groups- on the basis of size of macrolide ring
4.
© Ramaiah University
ofApplied Sciences 4 FacultyofPharmacy Antifungal antibiotics • 26-membered–ring polyenes, such as natamycin (pimaricin) form one group • 38-membered macrocycles, such as amphotericin B and nystatin, form other group • Number of double bonds in the macrocyclic ring differs also • Natamycin, the smallest macrocycle, is a pentaene; • Nystatin is a hexaene; and • Amphotericin B is a heptaene • polyenes have no activity against bacteria, rickettsia, or viruses • Highly potent, broad-spectrum antifungal agents
5.
© Ramaiah University
ofApplied Sciences 5 FacultyofPharmacy Antifungal antibiotics • Use of the polyenes for the treatment of systemic infections is limited • toxicities of the drugs, • Low water solubilities, and • poor chemical stabilities • Amphotericin B, the only polyene useful for the treatment of serious systemic infections, must be solubilized with a detergent • Other polyenes are indicated only as topical agents for superficial fungal infections
6.
© Ramaiah University
ofApplied Sciences 6 FacultyofPharmacy
7.
© Ramaiah University
ofApplied Sciences 7 FacultyofPharmacy Mechanism of action • In three-dimensional shape, • a barrel-like nonpolar structure capped by a polar group (sugar) • penetrate the fungal cell membrane, acting as “false membrane components,” • bind closely with ergosterol, • causing membrane disruption, • cessation of membrane enzyme activity, and • loss of cellular constituents, especially potassium ions
8.
© Ramaiah University
ofApplied Sciences 8 FacultyofPharmacy Amphotericin B • Purified from the fermentation beer of a soil culture of the actinomycete Streptomyces nodosus, which was isolated in Venezuela • first isolate from the streptomycete was a separable mixture of two compounds, designated amphotericins A and B • In test cultures, compound B proved to be more active, and this is the one used clinically • Amphotericin B is believed to interact with membrane sterols (ergosterol in fungi) to produce an aggregate that forms a transmembrane channel • Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl, and amino groups stabilize the channel in its open form
9.
© Ramaiah University
ofApplied Sciences 9 FacultyofPharmacy Amphotericin B • Destroying symport activity and allowing the cytoplasmic contents toleak out • This explains the toxicity in human patients • Is an amphoteric substance, with a primary amino group attached to the mycosamine ring and a carboxyl group on the macrocycle • Forms deep yellow crystals that are sparingly soluble in organic solvents but insoluble in water • To create a parenteral dosage form, amphotericin B is stabilized as a buffered colloidal dispersion in micelles with sodium deoxycholate • Nearly 80% of patients treated with amphotericin B develop nephrotoxicity
10.
© Ramaiah University
ofApplied Sciences 10 FacultyofPharmacy Amphotericin B • Fever, headache, anorexia, gastrointestinal distress, malaise, and muscle and joint pain are common • Pain at the site of injection and thrombophlebitis are frequent complications of intravenous administration. • Drug must never be administered intramuscularly. • Hemolytic activity of amphotericin B may be a consequence of its ability to leach cholesterol from erythrocyte cell membranes • For fungal infections of the CNS (e.g., cryptococcosis), amphotericin B is mixed with cerebrospinal fluid (CSF) that is obtained from a spinal tap
11.
© Ramaiah University
ofApplied Sciences 11 FacultyofPharmacy
12.
© Ramaiah University
ofApplied Sciences 12 FacultyofPharmacy Amphotericin B • Drug is supplied in various topical forms, including a 3% cream, a 3% lotion, a 3% ointment, and a 100-mg/mL oral suspension • Nystatin • First isolated in 1951 from a strain of the actinomycete Streptomyces noursei by Hazen and Brown • very slightly soluble in water and sparingly soluble in organic solvents • unstable to moisture, heat, and light • aglycone portion of nystatin is called nystatinolide
13.
© Ramaiah University
ofApplied Sciences 13 FacultyofPharmacy Nystatin • It consists of a 38-membered macrolide lactone ring containing single tetraene and diene moieties separated by two methylene groups • Aglycone also contains eight hydroxyl groups, one carboxyl group, and the lactone ester functionality • Entire compound is constructed bylinking the aglycone to mycosamine • not absorbed systemically when administered by the oral route • It is nearly insoluble under all conditions • It is also too toxic to be administered parenterally and used only as a topical agent
14.
© Ramaiah University
ofApplied Sciences 14 FacultyofPharmacy Nystatin • Valuable agent for the treatment of local and gastrointestinal monilial infections caused by C. albicans and other Candida species • For the treatment of cutaneous and mucocutaneous candidiasis, it is supplied as a cream, an ointment, and a powder • Oral tablets are used in the treatment of gastrointestinal and oral candidiasis
15.
© Ramaiah University
ofApplied Sciences 15 FacultyofPharmacy Natamycin
16.
© Ramaiah University
ofApplied Sciences 16 FacultyofPharmacy Natamycin • Polyene antibiotic obtained from cultures of Streptomyces natalensis • consistsof a 26-membered lactone ring containing a tetraene chromophore, • an α,β-unsaturated lactone carbonyl group, three hydroxyl groups, a carboxyl group, a trans epoxide, and a glycosidically joined mycosamine • natamycin is amphoteric • Mechanism- 26-membered–ring polyenes cause both potassium ion leakage and cell lysis at the same concentration • whereas the 38-membered–ring polyenes cause potassium leakage at low, fungistatic concentrations and cell lysis at high, fungicidal concentrations
17.
© Ramaiah University
ofApplied Sciences 17 FacultyofPharmacy Natamycin • smaller polyenes are fungistatic and fungicidal within the same concentration range • supplied as a 5% ophthalmic suspension intended for the treatment of fungal conjunctivitis, blepharitis, and keratitis • Griseofulvin • antibiotic obtained from the fungus Penicillium griseofulvum • It was isolated originally as a “curling factor” in plants • drug has been used for many years for its antifungal action in plants and animals • In 1959, griseofulvin was introduced into human medicine for the treatment of tinea infections by the systemic route
18.
© Ramaiah University
ofApplied Sciences 18 FacultyofPharmacy Griseofulvin
19.
© Ramaiah University
ofApplied Sciences 19 FacultyofPharmacy Griseofulvin • example of a rare structure in nature, a spiro compound • compound is a white, bitter, heat-stable powder or crystalline solid • sparingly soluble in water but soluble in alcohol and other nonpolar solvents • used for a long time for the systemically delivered treatment of refractory ringworm infections of the body, hair, nails, and feet • caused by species of dermatophytic fungi including Trichophyton, Microsporum and Epidermophyton • Griseofulvin neither possesses antibacterial activity nor is effective against P. obiculare, the organism that causes tinea versicolor
20.
© Ramaiah University
ofApplied Sciences 20 FacultyofPharmacy Griseofulvin • most common ones are allergic reactions such as rash and urticaria, gastrointestinal upset, headache, dizziness, and insomnia • oral bioavailability of griseofulvin is very poor • compound is highly lipophilic with low water solubility • Several structural derivatives have been synthesized, but they have failed to improve absorption • best advice that the pharmacist can give a patient who is about to use griseofulvin is to take the drug with a fatty meal
21.
© Ramaiah University
ofApplied Sciences 21 FacultyofPharmacy Synthetic anti-fungal agents • Clotrimazole, Econazole, Butoconazole, Oxiconazole Tioconozole Ketoconazole, Terconazole, Itraconazole, Fluconazole, Naftifine hydrochloride • Synthesis- Miconazole, Tolnaftate • Azole Antifungal Agents • Possess a unique mechanism of action • Can achieve selectivity for the infecting fungus over the host • Can treat infections ranging from simple dermatophytoses to life-threatening, deep systemic fungal infections • First members of the class were highly substituted imidazoles, such as clotrimazole and miconazole
22.
© Ramaiah University
ofApplied Sciences 22 FacultyofPharmacy Azole Antifungal Agents • Structure–activity studies revealed that the imidazole ring could be replaced with a bioisosteric 1,2,4-triazole ring without adversely affecting the antifungal properties of the molecule • Spectrum of activity • Azoles tend to be effective against most fungi that cause superficial infections of the skin and mucous membranes, including the dermatophytes such as Trichophyton, Epidermophyton, and Microsporum spp. and yeasts such as C. albicans • On the other hand, they also exhibit activity against yeasts that cause systemic infections, including C. immitis, C. neoformans, Paracoccidioides brasiliensis, Petriellidium boydii, B. dermatitidis, and H. capsulatum
23.
© Ramaiah University
ofApplied Sciences 23 FacultyofPharmacy Azole Antifungal Agents- Mechanism of action • At micromolar, the azoles are fungicidal • At nanomolar, the azoles are fungistatic • Fungicidal effect is clearly associated with damage to the cell membrane, with the loss of essential cellular componentssuch as potassium ions and amino acids • Fungistatic effect is associated with inhibition of membrane-bound enzymes • A cytochrome P450-class enzyme, lanosterol 14α-demethylase, is the likely target for the azoles • Function of lanosterol 14α-demethylase is to oxidatively remove a methyl group from lanosterol during ergosterol biosynthesis
24.
© Ramaiah University
ofApplied Sciences 24 FacultyofPharmacy Azole Antifungal Agents- Mechanism of action
25.
© Ramaiah University
ofApplied Sciences 25 FacultyofPharmacy Azole Antifungal Agents- Mechanism of action • Lanosterol 14α-demethylase is also required for mammalian biosynthesis of cholesterol, and the azoles are known to inhibit cholesterol biosynthesis • Higher concentrations of the azoles are needed to inhibit the mammalian enzyme • Provides selectivity for antifungal action • 1,2,4-triazoles appear to cause a lower incidence of endocrine effects and hepatotoxicity than the corresponding imidazoles • Possibly because of a lower affinity for the mammalian cytochrome P450 enzymes involved
26.
© Ramaiah University
ofApplied Sciences 26 FacultyofPharmacy Clotrimazole • Broad-spectrum antifungal drug that is used topically for the treatment of tinea infections and candidiasis • It occurs as a white crystalline solid that is sparingly soluble in water but soluble in alcohol and most organic solvents • It is a weak base that can be solubilized by dilute mineral acids • Extremely stable, with a shelf life of more than 5 years • Effective against various pathogenic yeasts and • Reasonably well absorbed orally, extensively protein bound • Not considered suitable for the treatment of systemic infections
27.
© Ramaiah University
ofApplied Sciences 27 FacultyofPharmacy Econazole • It is only slightly soluble in water and most organic solvents • Used as a 1% cream for the topical treatment of local tinea infections and cutaneous candidiasis
28.
© Ramaiah University
ofApplied Sciences 28 FacultyofPharmacy Butoconazole • Extremely broad-spectrum antifungal drug that is specifically effective against C. albicans • It is intended for the treatment of vaginal candidiasis- 2% of butoconazole nitrate in the form of cream
29.
© Ramaiah University
ofApplied Sciences 29 FacultyofPharmacy Oxiconazole • It is used in cream and lotion dosage forms in 1% concentration for the treatment of tinea pedis, tinea corporis, and tinea capitis
30.
© Ramaiah University
ofApplied Sciences 30 FacultyofPharmacy Tioconazole • Used for the treatment of vulvovaginal candidiasis • A vaginal ointment containing 6.5% of the free base is available • More effective against Torulopsis glabrata than are other azoles
31.
© Ramaiah University
ofApplied Sciences 31 FacultyofPharmacy Miconazole • Occurs as white crystals that are sparingly soluble in water and most organic solvents • The free base is available in an injectable form, solubilized with polyethylene glycol and castor oil, and intended for the treatment of serious systemic fungal infections • Like candidiasis, coccidioidomycosis, cryptococcosis, petriellidiosis, and paracoccidioidomycosis • thrombophlebitis, pruritus, fever, and gastrointestinal upset are relatively common side effects
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ofApplied Sciences 32 FacultyofPharmacy Ketoconazole • broad-spectrum imidazole antifungal agent that is administered orally for the treatment of systemic fungal infections • It is a weakly basic compound that occurs as a white crystalline solid that is very slightly soluble in water
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ofApplied Sciences 33 FacultyofPharmacy Ketoconazole • primary route of excretion is enterohepatic • It is estimated to be 95% to 99% bound to protein in the plasma • Hepatotoxicity- most serious adverse effect • known to inhibit cholesterol biosynthesis in both mammals and fungi • High doses have also been reported to lower testosterone and corticosteronelevels • Ketoconazole is a racemic compound, consisting of the cis-2S,4R and cis-2R,4S isomers • trans-isomers, 2S,4S and 2R,4R, are much less active
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ofApplied Sciences 34 FacultyofPharmacy Ketoconazole • recommended for the treatment of the following systemic fungal infections: candidiasis (including oral thrush and the chronic mucocutaneous form), coccidioidomycosis, blastomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis • It is also used orally to treat severe refractory cutaneous dermatophytic infections not responsive to topical therapy or oral griseofulvin • antifungal actions of ketoconazole and the polyene antibiotic amphotericin B are reported to antagonize each other • used topically in a 2% concentration in a cream and in a shampoo for the management of cutaneous candidiasis and tinea infections
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ofApplied Sciences 35 FacultyofPharmacy Terconazole • Triazole derivative that is used exclusively for the control of vulvovaginal moniliasis caused by C. albicans and other Candida species • It is available in creams containing 0.4% and 0.8% of the free base intended for 7-day and 3-day treatment periods, respectively
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ofApplied Sciences 36 FacultyofPharmacy Itraconazole • Unique member of the azole class that contains two triazole moieties in its structure • A weakly basic 1,2,4-triazole and a non-basic 1,2,4-triazol-3-one • orally active, broad-spectrum antifungal agent and important alternative to ketoconazole
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ofApplied Sciences 37 FacultyofPharmacy Itraconazole • An acidic environment is required for optimum solubilization and oral absorption • Food greatly enhances the absorption of itraconazole, nearly doubling its oral bioavailability • drug is avidly bound to plasma proteins (nearly 99% at clinically effective concentrations)and extensively metabolized in the liver • Only one of the numerous metabolites, namely 1-hydroxyitraconazole, has significant antifungal activity • terminal elimination half-life of itraconazole ranges from 24 to 40 hours
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ofApplied Sciences 38 FacultyofPharmacy Itraconazole • Used for the treatment of systemic fungal infections including blastomycosis, histoplasmosis(including patients infected with [HIV]), • nonmeningeal coccidioidomycosis, paracoccidioidomycosis, and sporotrichosis • It may also be effective in the treatment of pergellosis, disseminated and deep organ candidiasis, coccidioidal meningitis, and cryptococcosis • Unlike ketoconazole, it is not hepatotoxic and does not cause adrenal or testicular suppression in recommended therapeutic doses
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ofApplied Sciences 39 FacultyofPharmacy Fluconazole • Water soluble bis-triazole with broad-spectrum antifungal properties • Suitable for both oral and intravenous administration as the free base • Excellent bioavailability in both tablet and suspension dosage forms • Presence of two weakly basic triazole rings in the molecule confers sufficient aqueous solubility to balance the lipophilicity of the 2,4-difluorophenyl group • Has a relatively long elimination half-life, ranging from 27 to 34 hours • It penetrates well into all body cavities, including the CSF • Little or no hepatic metabolism and is excreted substantially unchanged in the urine • Plasma protein binding of fluconazole is less than 10%
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ofApplied Sciences 40 FacultyofPharmacy Fluconazole • Inhibition of cytochrome P450 oxidases by fluconazole can give rise to clinically significant interactions involving increased plasma levels of cyclosporine, phenytoin, and the oral hypoglycemic drugs • Recommended for the treatment and prophylaxis of disseminated and deep organ candidiasis • It is also used to control esophageal and oropharyngeal candidiasis • Agent of choice for the treatment of cryptococcalmeningitis and for prophylaxis against cryptococcosis in AIDS patients
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ofApplied Sciences 41 FacultyofPharmacy Naftifine Hydrochloride • White crystalline powder that is soluble in polar solvents such as ethanol and methylene chloride • It is supplied in a 1% concentration in a cream and in a gel for the topical treatment of ringworm, athlete’s foot, and jock itch • Although unapproved for these uses, naftifine has shown efficacy for treatment of ringworm of the beard, ringworm of the scalp, and tinea versicolor Cl
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ofApplied Sciences 42 FacultyofPharmacy Tolnaftate • White crystalline solid that is insoluble in water, sparingly soluble in alcohol, and soluble in most organic solvents • compound, a thioester of β-naphthol, is fungicidal against dermatophytes, such as Trichophyton, Microsporum, and Epidermophyton spp., that cause superficial tinea infections • Available in a concentration of 1% in creams, powders, aerosols, gels, and solutions for the treatment of ringworm, jock itch, and athlete’s foot • Shown to act as an inhibitor of squalene epoxidase • in susceptible fungi
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ofApplied Sciences 43 FacultyofPharmacy Miconazole- Synthesis Miconazole -HBr Reductionof ketone to alcohol -HBr 2,4-dichlorophenacylbromide imidazole 2,4-dichlorobenzylbromide
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ofApplied Sciences 44 FacultyofPharmacy Tolnaftate- Synthesis 2-naphthol and thiophosgene to make a monosubstitutedproduct of thiophosgene, which is then reacted with N-methyl-3-toluidine to give the desired tolnaftate
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