Nystatin Are Used Topically to Treat Such Infections

Pharmaceutical Chemistry

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Synthesis of Essential Drugs By R.S. Vardanyan and V.J. Hruby, Elsevier, 2006 1 35. Antifungal Drugs

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 ineffective against pathogenic fungi.

Fungal infections (mycoses) occur less than bacterial or viral infections.

A few fungal infections can spread to the surface of the body and cause local disturbances, while others can be systemic and life threatening.

Some of these organisms (for example, Candida) can spread from a superficial location to internal organs, leading to systemic diseases with serious complications.

Fungal (mycotic) infections cause a lot of discomfort, and as a rule, are difficult to cure.

2 Fungal infections are conventionally divided into three categories: dermatophylic, mucocutaneous, and systemic.

1. Dermatophytic infections are the most widespread, which include skin, hair, and nails.

Most infections can be cured by using topical drugs, such as tolnaftate, undecylenic acid, haloprogin, clotrimazole, and miconazole. Griseofulvin is used orally for deep infections, in particular for infections of the nail bed. Ketoconazole is widely used for treating chronic dermatophytes.

2. Mucocutaneous infections caused primarily by the fungus Candida albicans occur in regions of moist skin and mucous membranes (i.e. gastrointestinal tract, perianal, and vulvovaginal areas).

Amphotericin B, miconazole, clotrimazole, and nystatin are used topically to treat such infections. For chronic infections, ketoconazole is taken orally.

3 3. Systemic infections are very rare, although they do present a serious problem since they are naturally chronic and difficult to diagnose and treat. So, antifungal drugs are medications used to treat fungal infections such as athlete’s foot, ringworm, and candidiasis (thrush) as well as serious systemic infections like cryptococcal meningitis.

Antifungals work by exploiting differences between mammalian and fungal cells to kill the fungal organism and without significantly harming the host.

From the medical point of view, antifungal drugs are considered dermatophytic, mucocutaneous, and systemic.

From the chemical point of view, antifungal drugs can be divided into polyenes, imidazole and triazole derivatives, allylamines, and others.

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536 35. Antifungal Drugs

14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell-wall synthesis. These drugs also block steroid synthesis in humans. Allylamines (naftifine, terbinalfine, butenafine, amorolfine) inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis. Others: Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis. Flucytosine is an antimetabolite. From the medical point of view, antifungal drugs are considered dermatophytic, mucocutaneous, and systemic. 35.1 POLYENE ANTIFUNGAL DRUGS Drugs included in this group—amphotericin 35.1B, nystatin, POLYENEnatamycin, ANTIFUNGALare used DRUGSfor treating systemic and superficial infections. Polyenes bind with sterols in the fungal cell wall (ergosterol), causes the cell’sDrugscontents includedto inleak this outgroup—amphotericinand the cell dies B,. nystatin, natamycin, are used for treating systemic and superficial infections. Natamycin is used only for ophthalmologic superficial Human (and other animal) cellsinfectioncontain purposes.cholesterol rather than ergosterol so are much less susceptible. Amphotericin B: Amphotericin B, [1R(1R∗,3S∗,5R∗,6R∗,9R∗,11R∗,15S∗,16R∗,17R∗, 18S∗,19E∗,21E∗,23∗,25E∗,27E∗,29E∗,31E∗,33R∗,35S∗,36R∗,37S∗)]-33-[3-amino-3,6- Amphotericin B dideoxy-β-D-mannopyranosyl)-oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl- 13-oxo-14,39-dioxabicyclo [33.3.1]nonatraconta-19,21,23,25,27,29,31-hepten-36-carbox is made from the cultural fluidylic ofacidthe (35.1.1),actinomycete is a large polyeneStreptomyces antibiotic madenodosus from. theThis culturalcompound fluid of the actino- has a broad spectrum ofmyceteantifungal Streptomycesactivity, nodosusincluding[1–5]. Candida albicans, Leishmania brasiliensis, Mycobacterium leprae, Histoplasma capsulatum, Blastomyces dermatitidus, and Coccidioides immitis. OH CH3 O OH OH HO OOHOH OH OH O CH3 COOH

CH3 OH NH2 35.1.1 O OH 5 CH3

This compound has a broad spectrum of antifungal activity, including Candida albicans, Leishmania brasiliensis, Mycobacterium leprae, Histoplasma capsulatum, Blastomyces dermatitidus,and Coccidioides immitis. It possesses fungistatic and fungicidal activity depending on the dose used. The antifungal activity of amphotericin B is exhibited because it binds with sterols, in particular with ergosterol in the cellular membrane of sensitive fungi. This reaction makes pores in the membrane and increases the permeability of the membrane to small molecules, thus reducing the function of the membrane as an osmotic barrier and making the cells more sensitive to being destroyed. Amphotericin B is active against growing cells and cells that are dormant. However, this compound is not highly selective and reacts with host mammalian cells. Despite the many side effects, amphotericin B remains the primary drug for treating severe, acute systemic fungal infections. It is used for generalized fungal infections, such as candidomycosis, aspergillosis, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and pulmonary mycoses. Synonyms of this drug are amphocyclin, fungisone, fungilin, and others. It possesses fungistatic and fungicidal activity depending on the dose used. The antifungal activity of amphotericin B is exhibited because it binds with ergosterol in the cellular membrane of sensitive fungi.

This reaction makes pores in the membrane and increases the permeability of the membrane to small molecules, thus reducing the function of the membrane as an osmotic barrier and making the cells more sensitive to being destroyed.

Amphotericin B is active against growing cells and cells that are dormant.

Side effects: this compound is not highly selective and reacts with host mammalian cells.

Amphotericin B remains the primary drug for treating severe, acute systemic fungal infections, such as candidomycosis, aspergillosis, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and pulmonary mycoses.

Synonym: amphocyclin, fungisone, and fungilin

6 Nystatin ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 537 was isolated in 1949 from the products of the vital activity of the actinomycete Streptomyces noursei, and it was the first antifungal antibiotic to be discovered. It has a broad spectrum of activity.

The mechanism of antifungal activity is similar to the mechanism of action of amphotericin B. It is used for preventing and treating candida infections of the skin and mucous membranes. 35.2 Imidazoles (Triazoles) 537 It is also used for preventing the development of candidomycosis during prolonged treatment with penicillin drugs andNystatin:antibioticsNystatinof other is stereoisomericgroup, especially 33-[(3-amino-3,6-dideoxy-during oral use ofβ-D-mannopyranosyl) tetracycline antibiotics, levomecytinoxy]-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo, and others. [33.3.1] nonatriaconta-19,21,25,27,29,31-hexaen-36-carboxylic acid (35.1.2) [6–14].

Synonym: biofanal, moronal, nicporil, fazigin, and candex OH

CH3 O OH

HO OOHOH OH OH O CH3 HO COOH

CH3 OH NH2

35.1.2 O OH 7 CH3 Nystatin was isolated in 1949 from the products of the vital activity of the actinomycete Streptomyces noursei,and it was the first antifungal antibiotic to be discovered. This polyene antibiotic is structurally similar to amphotericin B. It has a broad spectrum of activity. The mechanism of antifungal activity is similar to the mechanism of action of amphotericin B. It is used for preventing and treating candida infections of the skin and mucous membranes. In terms of preventative action, it is used for preventing the development of candidomycosis during prolonged treatment with penicillin drugs and antibiotics of other group, especially during oral use of tetracycline antibiotics, levomecytin, and others. Synonyms of this drug are biofanal, moronal, nicporil, fazigin, candex, and others.

Natamycin: Natamycin, a mixture of stereoisomeric 22-[(3-amino-3,6-dideoxy-β-D- mannopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28-trioxatricy- clo[22.3.1.0.5,7]-octacosa-8,14,16,18,20,penten-25-carboxylic acid (35.1.3), like amphotericin and nystatin, is a polyene antibiotic that is isolated from the products of the vital activity of the actinomycete Streptomyces natalensis [15–17].

O O OH

CH3 O OH O HO COOH

NH2

35.1.3 O OH

CH3 The spectrum of its activity is somewhat narrower than that of amphotericin and nystatin, but at the same time, it is less toxic. It exhibits especially pronounced activity against a few strains of Fusarium and Cefalosporium. Natamycin is a drug for treating superficial fungal infections, and it is used only for ophthalmologic purposes. Synonyms of this drug are pimafucin, pimaricin, tennecetin, and others.

35.2 IMIDAZOLES (TRIAZOLES)

Some imidazole derivatives have turned out to be extremely beneficial for treating fungal infections. They are ketoconazole, miconazole, clotrimazole, econazole, butoconazole, and others. ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 537

35.2 Imidazoles (Triazoles) 537

Nystatin: Nystatin is stereoisomeric 33-[(3-amino-3,6-dideoxy-β-D-mannopyranosyl) oxy]-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo [33.3.1] nonatriaconta-19,21,25,27,29,31-hexaen-36-carboxylic acid (35.1.2) [6–14].

CH3 O OH

HO OOHOH OH OH O CH3 HO COOH

CH3 OH NH2

35.1.2 O OH

CH3 Nystatin was isolated in 1949 from the products of the vital activity of the actinomycete Streptomyces noursei,and it was the first antifungal antibiotic to be discovered. This polyene antibiotic is structurally similar to amphotericin B. It has a broad spectrum of activity. The mechanism of antifungal activity is similar to the mechanism of action of amphotericin B. It is used for preventing and treating candida infections of the skin and mucous Natamycin membranes. In terms of preventative action, it is used for preventing the development of candidomycosis during prolonged treatment with penicillin drugs and antibiotics of other is a polyene antibiotic thatgroup,is especiallyisolated from duringthe oralproducts use ofof tetracyclinethe vital activity antibiotics,of the levomecytin, and others. actinomycete StreptomycesSynonymsnatalensis of. this drug are biofanal, moronal, nicporil, fazigin, candex, and others.

The spectrum of its activity is somewhat narrower than that of amphotericin and nystatin, but Natamycin: Natamycin, a mixture of stereoisomeric 22-[(3-amino-3,6-dideoxy- -D- at the same time, it is less toxic. It exhibits especially pronounced activity against a few β strains of Fusarium and Cefalosporiummannopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28-trioxatricy-. clo[22.3.1.0.5,7]-octacosa-8,14,16,18,20,penten-25-carboxylic acid (35.1.3), like amphotericin Natamycin is a drug forandtreating nystatin,superficial is a polyenefungal antibioticinfections, that isand isolatedit is fromused theonly productsfor of the vital activity of ophthalmologic purposes.the actinomycete Streptomyces natalensis [15–17].

O Synonym: pimafucin, pimaricin, and tennecetin O OH

CH3 O OH O HO COOH

NH2

35.1.3 O OH

CH3 8 The spectrum of its activity is somewhat narrower than that of amphotericin and nystatin, but at the same time, it is less toxic. It exhibits especially pronounced activity against a few strains of Fusarium and Cefalosporium. Natamycin is a drug for treating superficial fungal infections, and it is used only for ophthalmologic purposes. Synonyms of this drug are pimafucin, pimaricin, tennecetin, and others.

35.2 IMIDAZOLES (TRIAZOLES)

Imidazole and triazole groups inhibit the enzyme cytochrome P450 14�-demethylase. This enzyme converts lanosterol to ergosterol, which is required in fungal cell-wall synthesis. These drugs also block steroid synthesis in humans.

Unlike amphotericin B, benzimidazole derivatives are active only against growing cells. This drug does not affect host cells because mammals use exogenic sterols for their vital functions.

9 Ketoconazole

It has a broad spectrum of antifungal activity, including many candida infections. It possesses fungicidal and fungistatic activity with respect to dermatophytes, yeast fungus, dimorphous fungi, and eumycetes.

It is also active with respect to staphylococci and streptococci. It is effective for chronic diseases, treating fungal infections of the gastrointestinal tract, sex organs, skin, hair, and nails.

It is used in combination with shampoo for treating and preventing mycelial fungi, seborrheic dermatitis, and dandruff.

Synonym: nizoral

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538 35. Antifungal Drugs

The antifungal activity of imidazole derivatives is currently explained by their ability to selectively raise the permeability of the membrane of fungal cells by interfering with the biosynthesis of sterins, in particular ergosterin, by inhibiting its synthesis and by changing the lipid content of the membrane. However, unlike amphotericin B, benzimidazole derivatives are active only against growing cells. This drug does not affect host cells because mammals use exogenic sterols for their vital functions.

Ketoconazole: Ketoconazole, cis-1-acetyl-4-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole- 1-ylmethyl)-1,3-dioxolan-4-ylmethyl]phenyl]piperazine (35.2.4), 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). 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) [18–21].

CH2OH 1. COCl O CH2 OH O O Cl C CH2 Br + CH OH Cl C CH2 Br CH2 OH N Cl Cl 2. 35.2.1 N H

CH OCO CH OSOCH 2 2 2 3 O 1. NaOH HO N N C CH O O O O 3 2.CH3SO2Cl Cl C CH2 N Cl C CH2 N N N Cl Cl 35.2.2 35.2.3

CH2O NNCCH3

O O Cl C CH2 N N Cl 35.2.4 11 Ketoconazole has a broad spectrum of antifungal activity, including many candida infections. It possesses fungicidal and fungistatic activity with respect to dermatophytes, yeast fungus, dimorphous fungi, and eumycetes. It is also active with respect to staphylococci and streptococci. It is effective for chronic diseases, treating fungal infections of the gastrointestinal tract, sex organs, skin, hair, and nails. It is used in combination with shampoo for treating and preventing mycelial fungi, seborrheic dermatitis, and dandruff. Synonyms of this drug are nizoral and others.

Miconazole: Miconazole, 1-[2,4-dichloro-β-[(2,4-dichlorobenzyl)oxy]phenethyl]-imidazole (35.2.7), like ketoconazol, is synthesized from 2,4-dichlorophenacylbromide, which is reacted ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 539

35.2 Imidazoles (Triazoles) 539

Miconazolewith imidazole to make 1-(2,4-dichlorobenzoylmethyl)-imidazole[2,4-dichloro-ω-(1-imidazolyl)-acetophenone] (35.2.5). Reducing the carbonyl group in this molecule with sodium It isborohydrideprimarily used givesexternally 1-(2,4-dichlorophenyl)-3-(1-imidazolyl)-ethanolfor candida and dermatophyte infections (35.2.6),of the andskin theand hydroxylvaginal candidosisgroup is as alkylatedwell as byfor acute 2,4-dichlorobenzylbromideinternal mycoses. using a powerful base such as sodium Synonymhydride :toacnidazil make miconazole, dactar, and (35.2.7)dermonistate [22–24].

O O NaBH N 4 Cl C CH2 Br + Cl C CH2 N N N Cl Cl H 35.2.5

Cl Cl CH2 Cl Br CH Cl OH 2 O Cl CH CH N 2 Cl CH CH2 N N N Cl Cl 35.2.6 35.2.7

Miconazole is primarily used externally for candida and dermatophyte infections of the12 skin and vaginal candidosis as well as for acute internal mycoses. Synonyms of this drug are acnidazil, dactar, dermonistate, and others.

Econazole: Econazole, 1-[2,4-dichloro-β-[(4-chlorobenzyl)oxy]phenethyl]-imidazole (35.2.8), is an analog of myconazole. It differs in the presence of a single chlorine atom in the benzyl part of the molecule, and it is synthesized in the same manner, except that it uses 4-chlorobenzylchloride in the last stage instead of 2,4-dichlorobenzylbromide [22–24].

CH2 Cl O

Cl CH CH2 N N Cl 35.2.8

Econazole is also used externally (only superficially) to treat ringworm and candidoses caused by flora that are sensitive to this drug (Trichophiton rubrum, Trichophiton menta-grophytes, Trichophiton tonsurans, Microsporum canis, Microsporum audouini, Microsporum gypseum, Candida albicans). When used locally, it kills fungi in three days. Synonyms of this drug are pevaryl, exostatin, dermazol, and others.

Sulconazole: Sulconazole, 1-[2,4-dichloro-β-[(4-chlorobenzyl)thio]phenethyl]-imidazole (35.2.9), is an analog of exonazole. It differs in the replacement of the etheral oxygen bridge (which connects the 4-chlorobenzyl part of the molecule with phenethylimidazole) for a thioether bond. The corresponding changes in the synthesis of this drug are the replacement of the hydroxyl group in 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)-ethanol (35.2.6) with a chlorine atom using thionyl chloride, followed by a reaction of the resulting chloride with 4-chlorobenzylmercaptane to make sulconazole [25,26]. ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 539

35.2 Imidazoles (Triazoles) 539

with imidazole to make 1-(2,4-dichlorobenzoylmethyl)-imidazole[2,4-dichloro-ω-(1-imidazolyl)-acetophenone] (35.2.5). Reducing the carbonyl group in this molecule with sodium borohydride gives 1-(2,4-dichlorophenyl)-3-(1-imidazolyl)-ethanol (35.2.6), and the hydroxyl group is alkylated by 2,4-dichlorobenzylbromide using a powerful base such as sodium hydride to make miconazole (35.2.7) [22–24].

O O NaBH N 4 Cl C CH2 Br + Cl C CH2 N N N Cl Cl H 35.2.5

Cl Cl CH2 Cl Br CH Cl OH 2 O Cl CH CH N 2 Cl CH CH2 N N N Cl Cl 35.2.6 35.2.7

Miconazole is primarily used externally for candida and dermatophyte infections of the skin and vaginal candidosis as well as for acute internal mycoses. Synonyms of this drug are acnidazil, dactar, dermonistate, and others.

Econazole: Econazole, 1-[2,4-dichloro-β-[(4-chlorobenzyl)oxy]phenethyl]-imidazole Econazole (35.2.8), is an analog of myconazole. It differs in the presence of a single chlorine atom in It is also used externally the(only benzylsuperficially) part of theto treat molecule,ringworm and andit is candidosessynthesizedcaused in the sameby manner, except that it ELSE_Vardanyan_CH035.qxdflora that are sensitive to uses1/19/2006this 4-chlorobenzylchloridedrug (Trichophiton 12:07 PM rubrum,Page in 540 theTrichophiton last stagementa instead-grophytes of 2,4-dichlorobenzylbromide, Trichophiton tonsurans, Microsporum[22–24]. canis, Microsporum audouini, Microsporum gypseum, Candida albicans). When used locally, it kills fungi in three days.

CH2 Cl Synonym: pevaryl, exostatin, and dermazol O

Cl CH CH2 N N Cl 35.2.8 Sulconazole540 35. Antifungal Drugs Econazole is also used externally (only superficially) to treat ringworm and candidoses caused Like econazole, it is used externallyby flora thatfor arethe sensitivesame indications to this drugas econazole(Trichophiton. rubrum, Trichophiton menta-grophytes, Trichophiton tonsurans, Microsporum canis, Microsporum audouini, Microsporum gypseum, CH2 Cl Synonym: exelderm and sulcosyn 2.HS CH Cl CandidaOH albicans). When used2 locally, it kills fungiS in three days. Synonyms of this drug are Cl CH CH N pevaryl, exostatin,2 dermazol, and others. Cl CH CH2 N N N Cl 35.2.6 Cl 35.2.9 13 Sulconazole: Sulconazole, 1-[2,4-dichloro-β-[(4-chlorobenzyl)thio]phenethyl]-imidazole Like econazole, sulconazole(35.2.9), is anis used analog externally of exonazole. (only superficially) It differs in for the the replacement same indications of the etheral oxygen as econazole. Synonymsbridge (which of this connects drug are the exelderm, 4-chlorobenzyl sulcosyn, part and of others.the molecule with phenethylimidazole) for a thioether bond. The corresponding changes in the synthesis of this drug are the Butoconazole: Butoconazole,replacement of 1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]- the hydroxyl group in 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)-ethanol 1H-imidazole (35.2.12),(35.2.6) iswith synthesized a chlorine from atom 4-chlorobenzylmagnesium using thionyl chloride, followed bromide, by whicha reaction is of the result- reacted with epichloridrineing chloride with to make 4-chlorobenzylmercaptane 4-(4Ј-chlorophenyl)-1-chlorobutan-2-ol to make sulconazole (35.2.10), [25,26]. which is reacted with imidazole in the presence of sodium to make 4-(4Ј-chlorophenyl)- 1-(1H-imidazolyl)butanol-2 (35.2.11). The hydroxyl group in the last is replaced with a chlorine atom upon reaction with thionyl chloride, which is then by the reaction with 2,6- dichlorothiophenol butoconazole [27,28], is obtained.

N O H/ Na Cl CH2MgBr + CH2 Cl ClCH2 CH2 CH CH2 Cl OH 35.2.10

1. SOCl2 ClCH2 CH2 CH CH2 N ClCH2 CH2 CH CH2 N N OH N Cl S 35.2.11 Cl Cl 35.2.12 2. SH

Butoconazole is a fungostatic drug, and it is formally classified as an imidazole, but only because of the presence of an imidazole ring in the structure. It is believed that butoconazole, like miconazole, econazole, and other “pure” representatives of the imidazole class, also inhibits the biosynthesis of estrosterin in the cytoplasmatic membrane of fungi; however, it is very possible that this is not the only mechanism of its action. It is effective for vaginal infections caused by various types of candida. It is also used only externally and vaginally. Synonyms of this drug are femstat, listomin, and others.

Terconazole: Terconazole, 1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)- 1,3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)-piperazine (35.2.19), is chemically very similar to ketoconazole, the only difference being that instead of an imidazole ring it contains a triazole ring and the piperazine ring, instead of an acetyl group is substituted by an isopropyl group. It is synthesized from 2,4-dichloroacetophenone, which is reacted with glycerol in the presence of p-toluenesulfonic acid to make a ketal, 2-(2,4-dichlorophenyl)- 2-methyl-4-hydroxymethyl-1,3-dioxolane (35.2.13). Brominating this with molecular bromine at the methyl group and then acylating the free hydroxyl group with benzoyl chloride gives 2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 540

540 35. Antifungal Drugs

CH2 Cl 2.HS CH Cl OH 2 S Cl CH CH N 2 Cl CH CH2 N N N Cl Cl 35.2.6 35.2.9

Like econazole, sulconazole is used externally (only superficially) for the same indications as econazole. Synonyms of this drug are exelderm, sulcosyn, and others.

Butoconazole: Butoconazole, 1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]- Butoconazole1H-imidazole (35.2.12), is synthesized from 4-chlorobenzylmagnesium bromide, which is reacted with epichloridrine to make 4-(4Ј-chlorophenyl)-1-chlorobutan-2-ol (35.2.10), It iswhicha fungostatic is reacteddrug, withinhibits imidazolethe biosynthesisin the presenceof estrosterin of sodiumin tothe makecytoplasmatic 4-(4Ј-chlorophenyl)-membrane of fungi. 1-(1H-imidazolyl)butanol-2 (35.2.11). The hydroxyl group in the last is replaced with a It chlorineis effective atomfor uponvaginal reactioninfections with causedthionyl bychloride,various whichtypes isof thencandida by the. It reactionis also usedwith 2,6-only externallydichlorothiophenoland vaginally butoconazole. [27,28], is obtained.

Synonym: femstat and listomin N N O H/ Na Cl CH2MgBr + CH2 Cl ClCH2 CH2 CH CH2 Cl OH 35.2.10

1. SOCl2 ClCH2 CH2 CH CH2 N ClCH2 CH2 CH CH2 N N OH N Cl S 35.2.11 Cl Cl 35.2.12 2. SH

Cl 14

35.2 Imidazoles (Triazoles) 541 Terconazole:

It is(35.2.14).effective for Reactingfungistatic this action with 1,2,4-triazolefor many strains in of theCandida presenceand ofdermatophytes sodium, followed. by It theinhibits hydrolysisthe action of theof protectingthe enzyme benzoyllanosterol group1 - withdemethylase sodium hydroxideof cytochrome gives P 2-(2,4--450 of sensitivedichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolanefungi, causing a reduction in the amount of ergosterin, which is necessary for the organisms(35.2.15).to Treatingconstruct thismembranes with methanesulfonyland to retain chloridethe appropriate gives thepermeability corresponding. mesylate It is35.2.16.only used externally for treating vulvovaginal candidoses.

Synonym: terazol and tercospor CH2OH CH2 OCO 2. COCl O CH2 OH O O O O Cl C CH3 + CH OH Cl C CH3 Cl C CH2 Br CH2 OH Cl Cl Cl 35.2.13 35.2.14

N CH2 OH CH2OSO2CH3 1. N N O O O O H N CH3SO2Cl N 2. Cl C CH2 N Cl C CH2 N NaOH N N Cl Cl 15 35.2.15 35.2.16

The way of making the second necessary fragment, 1-isopropyl-4-(4-hydroxyphenyl)- piperazine (35.2.18) is started from 4-(4-methoxyphenylpiperazine). Reducing this with hydrogen in the presence of acetone and using a palladium on carbon catalyst gives 1- isopropyl-4-(4-methoxyphenyl)piperazine (35.2.17). Treating of the resulting product with concentrated hydrobromic acid removes the protection from the phenol hydroxyl, making 1-isopropyl-4-(4-hydroxyphenyl)piperazine (35.2.18).

O CH CH H2 / Pd C 3 HBr 3 CH3ONNH+ CH3 CCH3 CH3ONNCH HO N N CH CH3 CH3

35.2.17 35.2.18

Finally, reacting the mesylate (35.2.16) with the resulting 1-isopropyl-4-(4-hydroxyphenyl)piperazine (35.2.18) gives the desired terconazole [29–32].

CH CH3 3 CH O NNCH CH2OSO2CH3 HO NNCH 2 CH CH3 3 O O O O N 32.2.18 N Cl C CH N Cl C CH2 N 2 N N Cl Cl 35.2.16 35.2.19 Terconazole is effective for fungistatic action for many strains of Candida and dermatophytes. The exact mechanism of its action is unknown, although it inhibits the action of the enzyme lanosterol 1-demethylase of cytochrome P-450 of sensitive fungi (similar to other azols described above), causing a reduction in the amount of ergosterin, which is necessary for the organisms to construct membranes and to retain the appropriate permeability. It is only used externally for treating vulvovaginal candidoses. Synonyms of this drug are terazol, tercospor, and others. ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 541

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35.2 Imidazoles (Triazoles) 541

(35.2.14). Reacting this with 1,2,4-triazole in the presence of sodium, followed by the hydrolysis of the protecting benzoyl group with sodium hydroxide gives 2-(2,4- 35.2 Imidazoles (Triazoles) 541 dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (35.2.15). Treating this with methanesulfonyl chloride gives the corresponding mesylate 35.2.16.(35.2.14). Reacting this with 1,2,4-triazole in the presence of sodium, followed by the hydrolysis of the protecting benzoyl group with sodium hydroxide gives 2-(2,4- dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane CH2OH CH2 OCO (35.2.15). Treating this with methanesulfonyl chloride2. givesCOCl the corresponding mesylate 35.2.16.O CH2 OH O O O O Cl C CH3 + CH OH Cl C CH3 Cl C CH2 Br CH2 OH Cl Cl Cl 35.2.13 35.2.14 CH2OH CH2 OCO 2. COCl O CH OH O O O O N 2 Cl C CH + CH OH ClCH2 OH C CH3 Cl CCH CH22OSOBr 2CH3 1. N 3 N CH2 OH Cl O O Cl OCl O H N 35.2.13 CH3SO2Cl 35.2.14 N 2. Cl C CH2 N Cl C CH2 N NaOH N N N Cl Cl CH2 OH CH2OSO2CH3 1. N 35.2.15 35.2.16 N O O O O H N CH3SO2Cl N 2. Cl C CH2 N Cl C CH2 N The way ofNaOH making the second necessaryN fragment, 1-isopropyl-4-(4-hydroxyphenyl)-N piperazine (35.2.18) is started Clfrom 4-(4-methoxyphenylpiperazine).Cl Reducing this with 35.2.15 35.2.16 hydrogen in the presence of acetone and using a palladium on carbon catalyst gives 1- isopropyl-4-(4-methoxyphenyl)piperazineThe way of making the second necessary (35.2.17). fragment, Treating 1-isopropyl-4-(4-hydroxyphenyl)- of the resulting product with concentratedpiperazine (35.2.18)hydrobromic is started acid fromremoves 4-(4-methoxyphenylpiperazine). the protection from the phenol Reducing hydroxyl, this makingwith 1-isopropyl-4-(4-hydroxyphenyl)piperazinehydrogen in the presence of acetone and using (35.2.18). a palladium on carbon catalyst gives 1- isopropyl-4-(4-methoxyphenyl)piperazine (35.2.17). Treating of the resulting product with

concentrated hydrobromicO acid removes the protection from theCH phenol hydroxyl, makingCH H2 / Pd C 3 HBr 3 + CH1-isopropyl-4-(4-hydroxyphenyl)piperazine3ONNHCH3 CCH3 CH3 ONNCH(35.2.18). HO N N CH CH3 CH3

35.2.17 35.2.18 O CH CH H2 / Pd C 3 HBr 3 CH3ONNH+ CH3 CCH3 CH3ONNCH HO N N CH Finally, reacting the mesylate (35.2.16) with the resultingCH3 1-isopropyl-4-(4-hydrox-CH3 yphenyl)piperazine (35.2.18) gives the desired terconazole35.2.17 [29–32]. 35.2.18 Finally, reacting the mesylate (35.2.16) with the resulting 1-isopropyl-4-(4-hydrox- CH yphenyl)piperazine (35.2.18) gives the desired terconazoleCH3 [29–32]. 3 CH O NNCH CH2OSO2CH3 HO NNCH 2 CH CH3 3 O O O O N 32.2.18 N CH3 CH3 Cl C CH2 N Cl C CH2 N CH O NNCH CH2OSON 2CH3 HO NNCH 2 N CH CH3 Cl 3 Cl O O O O35.2.16 N 32.2.18 35.2.19N Cl C CH N Cl C CH2 N 2 N N TerconazoleCl is effective for fungistatic action for many strainsCl of Candida and dermatophytes. The exact35.2.16 mechanism of its action is unknown, although35.2.19 it inhibits the action of the enzyme lanosterol 1-demethylase of cytochrome P-450 of sensitive fungi (similar to Terconazole is effective for fungistatic action for many strains of Candida and dermato-16 otherphytes. azols The described exact mechanism above), causingof its action a reduction is unknown, in the although amount it ofinhibits ergosterin, the action which of is necessarythe enzyme for lanosterolthe organisms 1-demethylase to construct of cytochromemembranes P-450and to of retain sensitive the appropriatefungi (similar perme- to ability.other Itazols is only described used externallyabove), causing for treating a reduction vulvovaginal in the amount candidoses. of ergosterin, Synonyms which of is this drugnecessary are terazol, for the tercospor, organisms and to constructothers. membranes and to retain the appropriate permeability. It is only used externally for treating vulvovaginal candidoses. Synonyms of this drug are terazol, tercospor, and others. ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 542

Clotrimazole

It also inhibits the biosynthesis of ergosterin in the cytoplasmatic membrane of fungi. In terms of pharmacological action, clotrimazole is very similar to miconazole.

It has542a broad spectrum of antifungal activity. It is effective with respect to dermatophytes, 35. Antifungaland Drugs it also has an antimicrobial effect against streptococci and staphylococci. It is also effective with respect to trichomonases. It is very widely used, both externally and vaginally for treating superficialClotrimazole:infections.Clotrimazole, 1-(o-chloro-α,α-diphenylbenzyl)imidazole (35.2.21), is synthesized by reacting 2-chlorotriphenylmethylchloride (35.2.20) with imidazole in the pres- Synonymence: ofcanesten triethylamine, empecid [33–37]., lotrimin, and micosporin

N H CCl C N N

Cl Cl

35.2.20 35.2.21 17 The starting substance 2-chlorotriphenylmethylchloride is made in various ways. In particular, chlorinating 2-chlorotoluene under light makes 2-chlorotrichloromethylbenzene (35.2.22), which is reacted with benzene in the presence of aluminum chloride to give 2-chlorotriphenylmethylchloride (35.2.20).

/ AlCl3 Cl2 CH3 CCl3 CCl

Cl Cl Cl

35.2.22 35.2.20

An alternative way of making 2-chlorotriphenylmethylchloride is a Grignard reaction between 2-chlorobenzolphenone and phenylmagnesium bromide, followed by substitution of the hydroxyl group in the resulting 2-chlorotriphenylmethylcarbinol (35.2.23) with a chlorine using thionyl chloride.

SOCl2 O + MgBr C OH CCl

Cl Cl Cl

35.2.23 35.2.20

And finally, reacting phosphorous pentachloride with 2-chlorobenzophenone gives 2Ј- chloro-1,1-dichlorodiphenylmethane (35.2.24), which is used for the alkylation of benzene in the presence of aluminum chloride and gives 2-chlorotriphenylmethylchloride (35.2.20).

/ A l C l 3 Cl PCl5 O CCl CCl

Cl Cl Cl

35.2.24 35.2.20 ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 542

542 35. Antifungal Drugs

Clotrimazole: Clotrimazole, 1-(o-chloro-α,α-diphenylbenzyl)imidazole (35.2.21), is synthesized by reacting 2-chlorotriphenylmethylchloride (35.2.20) with imidazole in the presence of triethylamine [33–37].

N H CCl C N ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 542 N

Cl Cl

35.2.20 35.2.21

The starting substance 2-chlorotriphenylmethylchloride is made in various ways. In par- ELSE_Vardanyan_CH035.qxdticular, chlorinating 1/19/2006 2-chlorotoluene 12:07 underPM Page light 542 makes 2-chlorotrichloromethylbenzene 542(35.2.22), which is reacted with benzene in the presence of aluminum 35. Antifungalchloride to Drugs give 2-chlorotriphenylmethylchloride (35.2.20).

Clotrimazole: Clotrimazole, 1-(o-chloro-α,α-diphenylbenzyl)imidazole (35.2.21), is syn- / AlCl3 thesized by reacting 2-chlorotriphenylmethylchlorideCl2 (35.2.20) with imidazole in the pres- CH ence of triethylamine [33–37].3 CCl3 CCl 542 35. Antifungal Drugs Cl Cl Cl N 35.2.22 Clotrimazole: Clotrimazole, 1-(o-chloro-Nα,α-diphenylbenzyl)imidazole35.2.20 (35.2.21), is synthesized by reacting 2-chlorotriphenylmethylchlorideH (35.2.20) with imidazole in the pres- CCl C N An alternativeence of triethylamine way of making[33–37]. 2-chlorotriphenylmethylchlorideN is a Grignard reaction between 2-chlorobenzolphenoneCl and phenylmagnesiumCl bromide, followed by substitution of the hydroxyl group in the resulting 2-chlorotriphenylmethylcarbinolN (35.2.23) with a chlorine using thionyl chloride.35.2.20 N 35.2.21 H CCl C N The starting substance 2-chlorotriphenylmethylchloride is madeN in various ways. In par- Cl ticular, chlorinating 2-chlorotolueneCl under light makes 2-chlorotrichloromethylbenzene SOCl2 + MgBr C OH CCl (35.2.22), which is Oreacted with35.2.20 benzene in the presence35.2.21 of aluminum chloride to give

2-chlorotriphenylmethylchlorideCl (35.2.20). Cl Cl The starting substance 2-chlorotriphenylmethylchloride is made in various ways. In par-

ticular, chlorinating 2-chlorotoluene under light 35.2.23 makes 2-chlorotrichloromethylbenzene35.2.20 / AlCl3 (35.2.22), which is reactedCl2 with benzene in the presence of aluminum chloride to give And 2-chlorotriphenylmethylchloride finally, reacting CH phosphorous3 (35.2.20). pentachlorideCCl3 with 2-chlorobenzophenoneCCl gives 2Ј-

chloro-1,1-dichlorodiphenylmethaneCl Cl (35.2.24), which is used for theCl alkylation of benzene

/ AlCl3 in the presence of aluminumCl chloride and gives 2-chlorotriphenylmethylchloride 2 35.2.22 (35.2.20). CH3 CCl3 35.2.20CCl An alternative way of Cl making 2-chlorotriphenylmethylchlorideCl Cl is a Grignard reaction

35.2.22 / A l C l 3 between 2-chlorobenzolphenone and phenylmagnesiumCl bromide, followed35.2.20 by substitution PCl5 of the hydroxyl groupO in the resulting 2-chlorotriphenylmethylcarbinolCCl CCl (35.2.23) with a chlorineAn using alternative thionyl way chloride. of making 2-chlorotriphenylmethylchloride is a Grignard reaction between 2-chlorobenzolphenoneCl andCl phenylmagnesium bromide, followedCl by substitution of the hydroxyl group in the resulting 2-chlorotriphenylmethylcarbinol (35.2.23) with a chlorine using thionyl chloride. 35.2.24 35.2.20 SOCl2 O + MgBr C OH CCl

Cl Cl Cl SOCl2 O + MgBr C OH CCl 35.2.23 35.2.20 Cl Cl Cl

And finally, reacting phosphorous pentachloride 35.2.23 with 2-chlorobenzophenone35.2.20 gives 2Ј- 18 chloro-1,1-dichlorodiphenylmethane (35.2.24), which is used for the alkylation of benzene in theAnd presence finally, reacting of aluminum phosphorous chloride pentachloride and gives with 2-chlorotriphenylmethylchloride 2-chlorobenzophenone gives 2Ј- (35.2.20).chloro-1,1-dichlorodiphenylmethane (35.2.24), which is used for the alkylation of benzene in the presence of aluminum chloride and gives 2-chlorotriphenylmethylchloride (35.2.20).

/ A l C l 3 Cl PCl5 O CCl / A l C l 3 CCl Cl PCl5 CCl CCl Cl O Cl Cl

Cl Cl Cl 35.2.24 35.2.20 35.2.24 35.2.20 ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 543

35.4 Others 543

Clotrimazole formally also is an imidazole derivative because of the presence of an imidazole ring in its structure. It is believed that, like miconazole, econazole, and other “pure” representatives of the imidazole class, it also inhibits the biosynthesis of ergosterin in the cytoplasmatic membrane of fungi. In terms of pharmacological action, clotrimazole is very similar to miconazole. It has a broad spectrum of antifungal activity. It is effective with respect to dermatophytes, and it also has an antimicrobial effect against streptococci and staphylococci. It is also effective with respect to trichomonases. It is very widely used, both externally and vaginally for treating superficial infections. Synonyms of this drug are canesten, empecid, lotrimin, 35.3 ALLYLAMINESmicosporin, and others. Allylamines (naftifine, terbinalfine, butenafine, amorolfine) inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol35.3 ALLYLAMINESsynthesis.

Naftifine is the first representative of a new class of antifungal drugs (naftifine, terbinafine Naftifine (lamisil), amorolfine, butenafine) classified as allylamines. It is only permitted to be used externally and only superficially as a drug with a broad spectrumNaftifine:of action againstNaftifine,dermatophytes (E)-N-methyl-N-(3-phenyl-2-propenyl)-1-naphthalinmethanamineand candida infections. It exceeds the activity of econazole(35.3.1),. Moreover, is synthesizedit does not byhave alkylatinga locally N-methyl-(1-naphthylmethyl)-amineirritating effect. with cinnamyl chloride in the presence of sodium carbonate [38–43]. Synonym: exoderil and naftin

CH3 Na2CO3 CH3 N N H + Cl

35.3.1

Naftifine is only permitted to be used externally and only superficially as a drug with19 a broad spectrum of action against dermatophytes and candida infections. According to the initial data, it exceeds the activity of econazole. Moreover, it does not have a locally irri- tating effect. It is believed that the fungicide activity of this drug is based on its ability to inhibit the fungal enzyme squalene epoxidase, thus lowering the concentration of ergosterol. The corresponding enzyme in mammals is inhibited significantly less. Synonyms of this drug are exoderil, naftin, and others.

35.4 OTHERS

Griseofulvin: Griseofulvin, 7-chloro-2Ј,4,6-trimethoxy-6Ј-methylspiro[benzofuran- 2(3H),1Ј-[2]-cyclohexen]-3Ј,4-dione (35.4.1), is an antibiotic produced by the mycelial fungus Penicillium patulum [44–51].

OCH3 O OCH3

O O CH3O Cl CH3 35.4.1 ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 543

35.4 Others 543

35.3 ALLYLAMINES

Naftifine is the first representative of a new class of antifungal drugs (naftifine, terbinafine (lamisil), amorolfine, butenafine) classified as allylamines.

Naftifine: Naftifine, (E)-N-methyl-N-(3-phenyl-2-propenyl)-1-naphthalinmethanamine (35.3.1), is synthesized by alkylating N-methyl-(1-naphthylmethyl)-amine with cinnamyl chloride in the presence of sodium carbonate [38–43].

CH3 Na2CO3 CH3 N N H + Cl

35.3.1

Naftifine is only permitted to be used externally and only superficially as a drug with a broad spectrum of action against dermatophytes and candida infections. According to the initial data, it exceeds the activity of econazole. Moreover, it does not have a locally irri- 35.4 OTHERS tating effect. It is believed that the fungicide activity of this drug is based on its ability to inhibit the fungal enzyme squalene epoxidase, thus lowering the concentration of ergos- Griseofulvin: terol. The corresponding enzyme in mammals is inhibited significantly less. Synonyms of It binds to polymerizedthis drug microtubulesare exoderil,and naftin,inhibits andfungal others.mitosis (causing the formation of multiple-nuclei, defective cells).

Flucytosine is an antimetabolite. It is used to treat35.4superficial OTHERSinfections includes dermatophyte infections of the skin, nails, and scalp.

It has a fungistaticGriseofulvin:effect on variousGriseofulvin,types of dermatophytes 7-chloro-2Ј,4,6-trimethoxy-6(trichophytes, microsporumsЈ-methylspiro[benzofuran-, achoriones, epidermophytones2(3H),1Ј-[2]-cyclohexen]-3). Ј,4-dione (35.4.1), is an antibiotic produced by the mycelial It is ineffective againstfungus deepPenicilliumsystemic patulummycotic infection,[44–51].and for candidomycoses.

It is only used orally. OCH3 O OCH3

Synonym: fulcin, licuden, and grifulvin O O CH3O Cl CH3 35.4.1 20 Flucytosine

It is a fluorinated derivative of pyrimidine. Its spectrum of activity is narrower than that of amphotericin B. It exhibits a synergetic effect when used in combination with amphotericin B for treating certain systemic fungal infections (subcutaneous chromobastomycosis). It is used intensively for treating systemic infections of the urinary tract that are caused by various strains of Candida.

In sensitive fungi, flucytosine is transformed into 5-fluorouracil and then turned into 5- fluorodeoxyuracilic acid, an inhibitor of thymidylate synthetase and DNA synthesis. 5- Fluorouracil triphosphate, which causes the formation of defective RNA, may also be involved in this process. The mechanism is highly selective because mammalian cells are not able to turn a large amount of flucytosine into 5-fluorouracil.

Synonym: ancobon and ancotil

21 ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 544

544 35. Antifungal Drugs

ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 544 Griseofulvin is an antifungal drug used to treat superficial infections. It has a fungistatic effect on various types of dermatophytes (trichophytes, microsporums, achoriones, epidermophytones). The antifungal activity is explained by its ability to inhibit cell mitosis in fungi, causing the formation of multiple-nuclei, defective cells. The spectrum of antifungal activity of griseofulvin includes dermatophyte infections of the skin, nails, and scalp. It is ineffective against deep systemic mycotic infection. It is also ineffective for candidomycoses.544 It is possible to develop resistance to it. 35. Antifungal Drugs It is primarily used for treating those suffering from favus, trichophytosis, mycrosporia of the hairy region of the head and smooth muscle, nail beds, and red epidermophyton. It Griseofulvin is an antifungal drug used to treat superficial infections. It has a fungistatic is onlyeffect used on orally. various Griseofulvin types of dermatophytes is only used in (trichophytes, the oral, medicinal microsporums, form. Synonyms achoriones, of this epi- drugdermophytones). are fulcin, licuden, The grifulvin, antifungal and activity others. is explained by its ability to inhibit cell mitosis in fungi, causing the formation of multiple-nuclei, defective cells. The spectrum of antifun- Flucytosine:gal activityFlucytosine, of griseofulvin 5-fluorocytosine includes dermatophyte (35.4.4), infections is synthesized of the skin, from nails, fluorouracil and scalp. (30.1.3.3).It is ineffective Fluorouracil against is reacted deep systemic with phosphorous mycotic infection. oxychloride It is also in dimethylaniline ineffective for tocan- makedidomycoses. 2,4-dichloro-5-fluoropyrimidine It is possible to develop (35.4.2), resistance which to isit. reacted with ammonia to make a productIt substituted is primarily with used chlorine for treating at the those fourth suffering position from of favus,the pyrimidine trichophytosis, ring—4-amino- mycrosporia 2-chloro-5-fluoropyrimidineof the hairy region of the (35.4.3). head and Hydrolysis smooth muscle, of the nailchlorovinyl beds, and fragment red epidermophyton. of this com- It poundis onlyin a solutionused orally. of hydrochloricGriseofulvin isacid only gives used the in desiredthe oral, flucytosine medicinal form. [52–55]. Synonyms of this drug are fulcin, licuden, grifulvin, and others. O Cl NH NH2 F 2 H N POCl F F H O / H C l F Flucytosine: Flucytosine,3 5-fluorocytosineN NH3 (35.4.4),N is2 synthesizedN from fluorouracil O N (30.1.3.3). Fluorouracil is Cl reactedN with phosphorousCl N oxychlorideO N in dimethylaniline to H make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted withH ammonia to make a 30.1.3.3 35.4.2 35.4.3 35.4.4 ELSE_Vardanyan_CH035.qxdproduct substituted 1/19/2006 with chlorine 12:07 at PM the Pagefourth 545 position of the pyrimidine ring—4-amino- An alternative2-chloro-5-fluoropyrimidine way of synthesis consists(35.4.3). ofHydrolysis making flucytosineof the chlorovinyl from a fragment precursor of of this fluo- com- rouracil—5-fluoro-2-methylthiouracilpound in a solution of hydrochloric (30.1.3.2) acid gives usingthe desired a somewhat flucytosine analogous [52–55]. scheme. Treating 5-fluoro-2-methylthiouracil (30.1.3.2) with phosphorous pentachloride gives O 4-chloro-5-fluoro-2-methylthiopyrimidineCl (35.4.5), whichNH upon being reactedNH2 with ammo- F 2 H N POCl F F H O / H C l F nium is transformed into 4-amino-5-fluoro-2-methylthiopyrimidine3 N NH3 N 2 (35.4.6).N Hydrolysis O N of the methylthiovinyl fragment usingCl NconcentratedCl hydrobromicN acidO givesN the desired H 35.4flucytosine Others [56–58]. H 545 30.1.3.3 35.4.2 35.4.3 35.4.4

OH Cl NH An alternative way of synthesis consists of making flucytosine2 from a precursorNH2 of fluo- F F F Flucytosine isN used withPCl amphotericin5 N for treatingNH3 certain systemicHBr fungal infections,F in rouracil—5-fluoro-2-methylthiouracil (30.1.3.2) usingN a somewhat analogousN scheme. particular CHfor3 treatingS N subcutaneousCH S chromobastomycosis.N It is used intensively for treat- Treating 5-fluoro-2-methylthiouracil3 (30.1.3.2)CH3 withS N phosphorous O pentachlorideN gives ing systemic infections of the urinary tract that are caused by various strains Hof Candida. 4-chloro-5-fluoro-2-methylthiopyrimidine30.1.3.2 35.4.5 (35.4.5), which 35.4.6 upon being reacted with ammo- Synonyms of this drug are ancobon, ancotil, and others. 35.4.4 nium is transformed into 4-amino-5-fluoro-2-methylthiopyrimidine (35.4.6). Hydrolysis Undecylenic acid Flucytosineof the methylthiovinyl is a fluorinated fragmentderivative using of pyrimidine. concentrated Its hydrobromicspectrum of activityacid gives is narrowerthe desired Undecylenic acid: Undecylenic acid, 10-undecylenic acid (35.4.7), is synthesized by thanIt is flucytosinevery that effective of amphotericin [56–58]. as an external B. drug However, for treating it exhibits moderate a dermatophyte synergetic effect infections when and used yeast in pyrolysiscombinationdermatitis, at but400°C with it is notand amphotericin effective low pressure for shingles B. (50 In sensitive mm) and foran candida oxyderivative fungi, infections. flucytosine of oleic is acid—ricinoleic transformed into acid—the glyceride ofOH which is the main Clingredient of castor oilNH [59,60]. 5-fluorouracil, which in turn is turned into 5-fluorodeoxyuracilic2 acid, an inhibitorNH2 of Synonym: benzevrine, micocidF , and undetin, F F N PCl5 N NH3 HBr F thymidylate synthetase, and correspondingly, DNA synthesis.N 5-Fluorouracil Ntriphosphate, t° CH3 S N CH S N H C CH (CH ) COOH + CH (CH ) CH O whichCH3 (CH)causes5 CH theCH 2formationCH CH (CH of2) 7defectiveCOOH3 RNA, may2 CHalso3 Sbe2 8 involvedN in 3thisO process.2 5N The OH H mechanism is highly30.1.3.2 selective because 35.4.5mammalian cells35.4.7 are 35.4.6not able to turn a large amount 35.4.4 22 of flucytosine into 5-fluorouracil. UndecylenicFlucytosine acid, is like a fluorinated zinc undecylenate, derivative is ofvery pyrimidine. effective Itsas anspectrum external of drug activity for treatingis narrower moderatethan dermatophyte that of amphotericin infections B.and However, yeast dermatitis, it exhibits but it ais synergeticnot effective effect for shingles when usedand in for candidacombination infections. with Synonyms amphotericin of this B. drug In sensitiveare benzevrine, fungi, micocid, flucytosine undetin, is transformed and others. into 5-fluorouracil, which in turn is turned into 5-fluorodeoxyuracilic acid, an inhibitor of Tolnaftate:thymidylateTolnaftate, synthetase, O-(2-naphthyl)-N-methyl-N-(3-tolyl)-thiocarbamate and correspondingly, DNA synthesis. 5-Fluorouracil (35.4.9), triphosphate, is syn- thesizedwhich by reacting causes theequimolar formation amounts of defective of 2-naphthol RNA, mayand thiophosgenealso be involved to make in this a monosub- process. The stitutedmechanism product of is thiophosgene highly selective (35.4.8), because which mammalian is then reacted cells are with not N-methyl-3-toluidine able to turn a large amount to give theof desiredflucytosine tolnaftate into 5-fluorouracil. [61–64].

CH3 N CH3 H CH3 OH O Cl ON CH3 S + C S S Cl Cl 35.4.9 35.4.8

Tolnaftate is used as an external drug for moderate dermatophyte infections (shingles), and it is not effective for treating candida infections. Synonyms of this drug are tinatox, tonof- tal, timoped, tinaderm, tinactin, and others.

Haloprogin: Haloprogin, 3-iodo-2-propinyl-2,4,5-trichlorophenyl ether (35.4.11), is synthesized by an iodide substitution using a mixture of iodine and potassium iodide and a cupric derivative of 2,4,5-trichlorophenylpropargyl ether (35.4.10), which is synthesized by a standard method from propargyl bromide and 2,4,5-trichlorophenol in the presence of sodium hydroxide [65–67].

Cl Cl 1. [Cu(NH3)2]Cl2 / (NH4)2CO3 Cl NaOH 2. I2 / KI Cl OH + Br CH2CCH Cl OCH2CCH Cl OCH2CC I

Cl Cl 35.4.10Cl 35.4.11

Haloprogin is used as an external drug for moderate dermatophyte infections (shingles), and it is effective for superficial candida infections. Synonyms of this drug are halotex, mycilan, micanden, and others. ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 545

35.4 Others 545

ELSE_Vardanyan_CH035.qxd 1/19/2006 12:07 PM Page 545 Flucytosine is used with amphotericin for treating certain systemic fungal infections, in particular for treating subcutaneous chromobastomycosis. It is used intensively for treating systemic infections of the urinary tract that are caused by various strains of Candida. Synonyms of this drug are ancobon, ancotil, and others.

Undecylenic acid: Undecylenic acid, 10-undecylenic acid (35.4.7), is synthesized by pyrolysis35.4 at 400°C Others and low pressure (50 mm) an oxyderivative of oleic acid—ricinoleic545 acid—the glyceride of which is the main ingredient of castor oil [59,60]. Flucytosine is used with amphotericin for treating certain systemic fungal infections, in ° particular for treating subcutaneous tchromobastomycosis.H C CH (CH ) COOH It is used+ CH intensively(CH ) CH for O treat- CH3 (CH)5 CH CH2 CH CH (CH2)7 COOH 2 2 8 3 2 5 ing systemicOH infections of the urinary tract that are caused by various strains of Candida. Synonyms of this drug are ancobon, ancotil, and 35.4.7others. Undecylenic acid, like zinc undecylenate, is very effective as an external drug for treating moderateUndecylenic dermatophyte acid: infectionsUndecylenic and yeast acid, dermatitis, 10-undecylenic but it is not acid effective (35.4.7), for is shingles synthesized and by pyrolysis at 400°C and low pressure (50 mm) an oxyderivative of oleic acid—ricinoleic for candida infections. Synonyms of this drug are benzevrine, micocid, undetin, and others. acid—the glyceride of which is the main ingredient of castor oil [59,60].

° t H C CH (CH ) COOH + CH (CH ) CH O Tolnaftate: CHTolnaftate,3 (CH)5 CH O-(2-naphthyl)-N-methyl-N-(3-tolyl)-thiocarbamateCH2 CH CH (CH2)7 COOH 2 2 8 (35.4.9),3 2 is5 syn- OH thesized by reacting equimolar amounts of 2-naphthol and thiophosgene35.4.7 to make a monosub- stituted product of thiophosgene (35.4.8), which is then reacted with N-methyl-3-toluidine to give the desiredUndecylenic tolnaftate acid, [61–64]. like zinc undecylenate, is very effective as an external drug for treating moderate dermatophyte infections and yeast dermatitis, but it is not effective for shingles and for candida infections. Synonyms of this drug are benzevrine, micocid, undetin, and others. CH3 N CH3 H CH Tolnaftate: Tolnaftate, O-(2-naphthyl)-N-methyl-N-(3-tolyl)-thiocarbamate (35.4.9),3 is syn- Tolnaftate OH O Cl ON CH3 S thesized+ by reacting equimolar amounts of 2-naphthol and thiophosgene to make a monosub- C S S It is used asstitutedan external productCl Cl ofdrug thiophosgenefor moderate (35.4.8),dermatophyte which is theninfections reacted with(shingles), N-methyl-3-toluidineand it is not to 35.4.9 effective forgivetreating the desiredcandida tolnaftateinfections [61–64].35.4.8. SynonymTolnaftate: tinatox is used, tonoftalas an external, timoped drug, tinaderm for moderate, and tinactin dermatophyte infections (shingles), and CH3 it is not effective for treating candida infections. SynonymsN of thisCH3 drug are tinatox, tonof- H tal, timoped, tinaderm, tinactin, and others. CH3 OH O Cl ON CH3 S + C S S Cl Cl 35.4.9 Haloprogin: Haloprogin, 3-iodo-2-propinyl-2,4,5-trichlorophenyl35.4.8 ether (35.4.11), is syn- Haloproginthesized by an iodide substitution using a mixture of iodine and potassium iodide and a Tolnaftate is used as an external drug for moderate dermatophyte infections (shingles), and It cupricis used derivativeas an external of 2,4,5-trichlorophenylpropargyldrug for moderate dermatophyte ether (35.4.10),infections which(shingles), is synthesizedand it is by a standardit is not method effective from for propargyl treating candida bromide infections. and 2,4,5-trichlorophenol Synonyms of this drug in the are presence tinatox, tonof-of effective fortal,superficial timoped,candida tinaderm,infections tinactin,. and others. sodium hydroxide [65–67]. Synonym: halotex, mycilan, and micanden

ClHaloprogin: Haloprogin, 3-iodo-2-propinyl-2,4,5-trichlorophenylCl 1. [Cu(NH3)2]Cl2 / (NH4)2CO3 ether Cl(35.4.11), is synthesized by an iodideNaOH substitution using a mixture2. I2 / KI of iodine and potassium iodide and a Cl OH + Br CH2CCH Cl OCH2CCH Cl OCH2CC I cupric derivative of 2,4,5-trichlorophenylpropargyl ether (35.4.10), which is synthesized Cl Cl Cl by a standard method from propargyl35.4.10 bromide and 2,4,5-trichlorophenol in the 35.4.11 presence23 of Haloproginsodium is used hydroxide as an external[65–67]. drug for moderate dermatophyte infections (shingles), and it is effective for superficial candida infections. Synonyms of this drug are halotex, Cl Cl 1. [Cu(NH3)2]Cl2 / (NH4)2CO3 Cl mycilan, micanden, and others. NaOH 2. I2 / KI Cl OH + Br CH2CCH Cl OCH2CCH Cl OCH2CC I

Cl Cl 35.4.10Cl 35.4.11