Anti-fungal antibiotics - Medicinal Chemistry III B. Pharma 6th Semester

Anti-fungal 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

       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

       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

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

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

       Destroying symport activity and allowing the cytoplasmic contents to leak 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

       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

 

       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

       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 by linking 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

       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

Natamycin

       Polyene antibiotic obtained from cultures of Streptomyces natalensis

       consists of 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

       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

       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

       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

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

       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

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 components such 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

       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

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

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

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

Oxiconazole

       It is used in cream and lotion dosage forms in 1% concentration for the treatment of tinea pedis, tinea corporis, and tinea capitis

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

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

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

       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 corticosterone levels

       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

       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

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

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

       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

       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

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%

       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 cryptococcal meningitis and for prophylaxis against cryptococcosis in AIDS patients

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

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

Miconazole- Synthesis

Tolnaftate- Synthesis

2-naphthol and thiophosgene to make a monosubstituted product of thiophosgene, which is then reacted with N-methyl-3-toluidine to give the desired tolnaftate

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