Description
Medicinal Chemistry-III
ANTI-FUNGAL ANTIB
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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
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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
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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
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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
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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
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AMPHOTERICIN B
• 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
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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
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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
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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 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
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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
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Natamycin
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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
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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
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GRISEOFULVIN
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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
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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
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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
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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
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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
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AZOLE ANTIFUNGAL AGENTS- MECHANISM OF ACTION
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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
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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
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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
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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
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OXICONAZOLE
• IT IS USED IN CREAM AND LOTION DOSAGE FORMS IN 1% CONCENTRATION FOR
THE TREATMENT OF TINEA PEDIS, TINEA CORPORIS, AND TINEA CAPITIS
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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
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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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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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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
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
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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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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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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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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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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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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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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 CRYPTOCOCCAL MENINGITIS AND
FOR PROPHYLAXIS AGAINST CRYPTOCOCCOSIS IN AIDS PATIENTS
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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
Cl
SHOWN EFFICACY FOR TREATMENT OF RINGWORM OF THE
BEARD, RINGWORM OF THE SCALP, AND TINEA VERSICOLOR
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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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MICONAZOLE- SYNTHESIS
-HBr
Reduction of
ketone to
alcohol
2,4-dichlorophenacylbromide imidazole
2,4-dichlorobenzylbromide
-HBr
Miconazole
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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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