Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry PDF

0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 191 Chapter 6 Anti-infective Agents 191 especially at pH greater than 7. Under these conditions, Potassium Sorbate...

0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 191 Chapter 6 Anti-infective Agents 191 especially at pH greater than 7. Under these conditions, Potassium Sorbate chlorobutanol undergoes elimination. Solutions with a pH Potassium sorbate occurs as a white crystalline material that of approximately 5 are reasonably stable at 25°C. is soluble in water and alcohol. It is used in the same way as Chlorobutanol is stable in oils and organic solvents. sorbic acid when greater water solubility is required. Benzyl Alcohol Benzyl alcohol (phenylcarbinol, phenylmethanol) occurs naturally as the unesterified form in oil of jasmine and in es- ters of acetic, cinnamic, and benzoic acids in gum benzoin, storax resin, Peru balsam, tolu balsam, and some volatile oils. It is soluble in water and alcohol and is a clear liquid Phenylmercuric Nitrate with an aromatic odor. Phenylmercuric nitrate is a mixture of phenylmercuric ni- Benzyl alcohol is commonly used as a preservative in trate and phenylmercuric hydroxide. It occurs as a white vials of injectable drugs in concentrations of 1% to 4% in crystalline material that is sparingly soluble in water and water or saline solution. Benzyl alcohol has the added ad- slightly soluble in alcohol. It is used in concentrations of vantage of having a local anesthetic action. It is commonly 1:10,000 to 1:50,000 to preserve injectable drugs against used in ointments and lotions as an antiseptic in the treat- bacterial contamination. A disadvantage to organomercuri- ment of various pruritic skin conditions. als is that their bacteriostatic efficacy is reduced in the pres- ence of serum. Phenylethyl Alcohol Phenylethyl alcohol (2-phenylethanol, orange oil, rose oil, C6H5CH2CH2OH) is a clear liquid that is sparingly soluble in water (⬃2%). It occurs naturally in rose oil and pine- needle oil. It is used primarily in perfumery. Benzoic Acid Benzoic acid and its esters occur naturally in gum benzoin and in Peru and tolu balsams. It is found as a white crys- talline solid that slowly sublimes at room temperature and is Phenylmercuric Acetate steam distillable. It is slightly soluble in water (0.3%) but Acetoxyphenylmercury occurs as white prisms that are sol- more soluble in alcohol and in other polar organic solvents. uble in alcohol but only slightly soluble in water. It is used It has a pKa of 4.2. Benzoic acid is used externally as an an- as a preservative. tiseptic in lotions, ointments, and mouthwashes. It is more effective as a preservative in foods and pharmaceutical products at low pH (less than the pKa). When used as a pre- servative in emulsions, its effectiveness depends on both pH and distribution into the two phases.16 ANTIFUNGAL AGENTS General Introduction to Fungi: Sodium Benzoate Medical Mycology Sodium benzoate is a white crystalline solid that is soluble The discovery that some infectious diseases could be attrib- in water and alcohol. It is used as a preservative in acidic uted to fungi actually preceded the pioneering work of liquid preparations in which benzoic acid is released. Pasteur and Koch with pathogenic bacteria by several years. Sodium Propionate Two microbiologists, Schönlein and Gruby, studied the fun- Sodium propionate occurs as transparent colorless crystals gus Trichophyton schoenleinii in 1839. In that same year, that are soluble in water and alcohol. It is an effective anti- Langenbeck reported the yeastlike microorganism responsi- fungal agent that is used as a preservative. Sodium propi- ble for thrush (C. albicans). Gruby isolated the fungus re- onate is most effective at low pH. sponsible for favus on potato slices, rubbed it on the head of a child, and produced the disease. Hence, he fulfilled Koch’s Sorbic Acid postulates 40 years before they were formulated.17 In spite 2,4-Hexadienoic acid is an effective antifungal preservative. of its earlier beginnings, medical mycology was quickly It is sparingly soluble in water and has a pKa of 4.8. Sorbic overshadowed by bacteriology, and it has only recently acid is used to preserve syrups, elixirs, ointments, and lo- begun to receive the serious attention that it deserves. This tions containing components such as sugars that support is perhaps attributable to the relatively benign nature of the mold growth. common mycoses, the rarity of the most serious ones, and the need for a morphological basis for differential identifi- cation of these structurally complex forms. Cursory examination shows that fungal infections fall into two well-defined groups: the superficial and the deep- 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 192 192 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry seated mycoses.18 The superficial mycoses are, by far, the cytomegalovirus also attack such patients. Multiple infec- most common and are caused, for the most part, by a rela- tions with various microorganisms are common. C. albicans tively homogeneous group of fungi, the dermatophytes. is a particularly common opportunist. This yeast is a mem- These include the various forms of tinea, or ringworm, ber of the normal microbial flora of human hosts, especially which are infections of the hair or hair follicles, the superfi- in the vagina. Use of contraceptives often predisposes a pa- cial infections of the intertriginous or flat areas of hairless tient to infection by Candida spp. Fungal flora that inhabit skin, and infections of the nails. As a rule, these lesions are the bowel may develop into a superinfection with the use of mild, superficial, and restricted. The causative microbes are antibiotics to sterilize the bowel before surgery. Oral can- specialized saprophytes with the unusual ability to digest didiasis is common in poorly nourished persons, in patients keratin. They have their ultimate reservoir in the soil. Unlike on immunosuppressive drugs, and in persons with acquired the deep-seated mycoses, however, they are frequently immunodeficiency syndrome (AIDS). Opportunists can transmitted from one host to another (e.g., athlete’s foot). A grow in nearly every circumstance in which a patient’s im- species of yeast, Candida, also produces a dermatophyte- mune system is compromised. like disease. Cutaneous Infections Systemic Mycoses (Dermatophytoses)22–24 The deep-seated, systemic mycoses have a sporadic distribu- By far, the most common types of human fungal disease are tion,19 being common in some parts of the world and un- among the dermatophytoses. These are superficial infections known in other geographical areas. These diseases have a of the keratinized epidermis and keratinized epidermal ap- heterogeneous etiology. Diseases caused by the systemic or- pendages (i.e., the hair and nails). The severity of an infection ganisms include histoplasmosis, sporotrichosis, blastomyco- depends largely on the location of the lesion and the species sis, coccidioidomycosis, cryptococcosis, and paracoccid- of the fungus involved. Though certain other fungi, notably ioidomycosis. The causative agents for these diseases are Candida spp., produce clinically similar diseases, a some- soil-inhabiting saprophytes with the ability to adapt to the in- what homogeneous group of fungi, termed the dermato- ternal environment of their host. These organisms share a phytes, is responsible for most cases. The ability of these or- common route of infection. Fungal spores are inhaled into ganisms to invade and parasitize the cornified tissues of hair, the lung, and a mild, coldlike condition may result. This may skin, and nails is closely associated with, and dependent on, be the only symptom. In most cases, disease is inapparent. In their common physiological characteristic—metabolic use of asymptomatic disease, diagnosis is often made serendipi- the highly insoluble scleroprotein keratin. The biochemical tously. Sensitization, which reflects present or previous ex- use of keratin is rare and is shared by the dermatophyte perience with the organism, may be detected by a skin test or species of the family Gymnoascaceae, with only a few other immunological procedure. The immune system deals species of the family Onygenaceae, and certain tineae. In hu- with these infections by walling them off or by producing mans, the genera Trichophyton (notably T. rubrum [nails, the giant cells that are common in type IV hypersensitivities. beard, smooth skin], T. tonsurans [scalp, beard, nails], T. vi- X-ray examination or autopsy frequently reveals these le- olaceum [scalp, skin nails], T. mentagrophytes [commonest sions. As stated previously, the causative organisms of the cause of athlete’s foot], T. verrucosum [scalp, beard], and T. systemic infections are not typically transmitted from one rubrum [psoriasis-like lesions of smooth skin, infections of host to another, but infection by the organism in an endemic nails]), Microsporum (M. gypseum [scalp], M. fulvum [scalp, area may be very common. Few infections develop into the hairless skin], and M. canis [scalp, hairless skin]), and severe, deep, spreading, and often-fatal disease seen in some Epidermophyton (eczema) contain the most common der- persons. If the infection is symptomatic, the clinical signs matophytes. These organisms cause the conditions known as may be those of a mild, self-limiting disease; or the infection tinea (ringworm). Some of the common tinea infections are may become progressive, with severe symptoms, tissue and listed in Table 6.4. The fungus Pityrosporum orbiculare organ damage, and, frequently, death. Recovery from a causes an additional type, tinea versicolor. This organism, deep-seated infection of this type is accompanied by an un- called Malassezia furfur in older literature, causes yellow to certain anamnestic immune response. brown patches or continuous scaling over the trunk and occa- sionally the legs, face, and neck. The affected areas may be Opportunistic Fungal Infections20,21 identified by the inability to tan in the sun. In recent years, because of overzealous use of antibacterial Regardless of the type of fungus that is causing an infec- antibiotics, the use of immunosuppressive agents, cytotox- tion (Table 6.5), treatment is extremely difficult because ins, irradiation, and steroids, a new category of systemic fungi, like mammalians, are eukaryotes. Many biochemical mycoses has become prominent. These are the opportunistic structures, especially the cell membranes, are nearly identi- fungal infections. There has been a precipitous rise in the in- cidence of these diseases. The patient, as a result of drug TABLE 6.4 Locations of the Common Types of Tinea therapy, underlying disease, or medical manipulation, is de- (Ringworm) prived of the normal defenses conferred by microbial flora. Type Location This allows organisms of normally low inherent virulence to exploit the host. Such infections include systemic candidia- Tinea manuum Hand sis, aspergillosis, and mucormycosis. Bacterial infections Tinea cruris Groin Tinea sycosis Beard such as Gram-negative septicemia, nocardiosis, and Tinea capitis Scalp Pseudomonas infection, fungal infections such as with Tinea unguium Nails Pneumocystis carinii, and viral opportunists such as 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 193 Chapter 6 Anti-infective Agents 193 TABLE 6.5 Clinical Types of Fungal Infection Type Disease State Causative Organism Superficial infections Tinea versicolor Pityrosporum orbiculare Piedra Trichosporon cutaneum (white) Piedraia hortae (black) Cutaneous infections Ringworm of scalp, hairless skin, nails Dermatophytes, Microsporum, Trichophyton, Epidermophyton Candidosis of skin, mucous membranes, Candida albicans and related forms nails; sometimes generalized Subcutaneous infections Chromomycosis Fonsecaea and related forms Mycotic mycetoma Allescheria boydii, Madurella mycetoma, etc. Entomophthoromycosis Basidiobolus haptosporus, Conidiobolus coronatus Systemic infections Histoplasmosis Histoplasma capsulatum Blastomycosis Blastomyces dermatiditis Paracoccidioidomycosis Paracoccidioides brasiliensis Coccidioidomycosis Coccidioides immitis Cryptococcosis Cryptococcus neoformans Sporotrichosis Sporothrix schenckii Aspergillosis Aspergillus fumigates Mucormycosis Mucor spp., Absidia spp., Rhizopus spp. Histoplasmosis duboisii Histoplasma capsulatum var. duboisii cal, as are many biochemical reactions. Consequently, drugs The causative agents are classified among several unrelated that will kill a fungus will have a toxic effect on human cells genera. They have the following characteristics in common: at normal doses. (a) they are primarily soil saprophytes of very low-grade A slight difference exists in the cell membranes. Lipid bi- virulence and invasive ability; and (b) in most human and layers by themselves are unstable and would be unable to animal infections, they gain access as a result of a trauma to hold their shape and support their functions. Sterols are em- the tissue. Many, if not all, organisms have the potential to bedded in the bilayers to act as stiffening agents. The 3-hy- establish local infections under certain circumstances, de- droxyl group represents the polar “head” group, and the non- pending on their adaptability and the response of the host. polar sterol skeleton and side chain align perfectly with the The tissue reaction in most cases varies with the agent in nonpolar chains of the bilayer. In human cells, the sterol in the question but usually remains a localized lesion similar to membrane is cholesterol (Fig. 6.1). In fungi, the sterol is er- that elicited by a foreign body. The major disease types are gosterol (Fig. 6.2). This difference amounts to the only source chromomycosis, sporotrichosis, mycetoma, lobomycosis, of selectivity that we have in treating fungal infections. New and entomophthoromycosis. A type of dimorphism accom- antifungal drug development has focused on this difference as panies infection by agents of some of these groups. The or- a way to achieve selectivity, creating highly potent antifungal ganisms undergo a morphogenesis from their saprophytic drugs that are much less toxic to the human host. form into a tissue or parasitic stage. Subcutaneous Fungal Infections22 Tissue Reactions of Fungal Disease23 Subcutaneous mycosis refers to a group of fungal diseases in The tissue response of the host to the infecting fungus which both the skin and subcutaneous tissue are involved varies widely and depends somewhat on various invasive but typically no dissemination to the internal organs occurs. organisms. In dermatophyte infections, erythema is gener- Figure 6.1 Cholesterol embedded in a lipid bilayer. 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 194 194 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry Figure 6.2 Ergosterol embedded in a lipid bilayer. ally produced and is a result of the irritation of the tissues in low concentration (⬃0.01%). Salt forms with sodium, by the organism. Sometimes, severe inflammation, fol- potassium, calcium, and ammonium are also fungicidal. lowed by scar tissue and keloid formation, occurs. This re- Propionic acid is a clear, corrosive liquid with a charac- sults from an exaggerated inflammatory response and an teristic odor. It is soluble in water and alcohol. The allergic reaction to the organism and its products. salts are usually used because they are nonvolatile and With organisms that invade living tissue, such as those odorless. responsible for subcutaneous and systemic disease, there is generally a uniform acute pyogenic reaction that gives way Zinc Propionate to various chronic disease outcomes. Granuloma with Zinc propionate occurs as an anhydrous form and as a caseation and fibrocaseous pulmonary granuloma are poten- monohydrate. It is very soluble in water but only sparingly tial outcomes of infection with Histoplasma capsulatum, soluble in alcohol. The salt is unstable to moisture, forming and thrombotic arteritis, a thrombosis characterized by a pu- zinc hydroxide and propionic acid. Zinc propionate is used rulent coagulative necrosis and invasion of blood vessels, as a fungicide, particularly on adhesive tape. may be caused during aspergillosis and mucormycosis. The Sodium Caprylate large numbers of fungal species of many morphotypes, their Sodium caprylate is prepared from caprylic acid, which is a disease etiology, and the diversity of outcomes make med- component of coconut and palm oils. The salt precipitates as ical mycology a complex field. cream-colored granules that are soluble in water and spar- ingly soluble in alcohol. Topical Agents for Dermatophytoses Collectively, the dermatophytoses are called tinea, or ring- worm. Since these infections tend to be topical, their treat- ment has been directed to surface areas of the skin. The skin is a formidable barrier to drug penetration, and many of the Sodium caprylate is used topically to treat superficial topical agents work best if an adjuvant is added that opens dermatomycoses caused by C. albicans and Trichophyton, the barrier function of the skin. Keratolytic agents such as Microsporum, and Epidermophyton spp. The sodium salt salicylic acid or other ␣-hydroxy compounds perform this can be purchased in solution, powder, and ointment forms. function reasonably well. Zinc Caprylate FATTY ACIDS Zinc caprylate is a fine white powder that is insoluble in water or alcohol. The compound is used as a topical fungi- Adults have an acidic, fatty substance in and on the skin cide. The salt is highly unstable to moisture. called sebum. Sebum functions as a natural antifungal agent, part of the innate immune system. Fatty acids have been Undecylenic Acid used for years with the idea that if a substance similar to 10-Undecenoic acid (Desenex, Cruex) obtained from sebum could be applied to the infected area, the effect of the the destructive distillation of castor oil. Undecylenic acid sebum would be augmented and fungi could be eradicated. is a viscous yellow liquid. It is almost completely insolu- The application of fatty acids or their salts does in fact have ble in water but is soluble in alcohol and most organic an antifungal effect, albeit a feeble one. solvents. The higher–molecular-weight fatty acids have the ad- vantage of having lower volatility. Salts of fatty acids are also fungicidal and provide nonvolatile forms for topical application. Propionic Acid Undecylenic acid is one of the better fatty acids for use Propionic acid is an antifungal agent that is nonirritating as a fungicide, although cure rates are low. It can be used in and nontoxic. After application, it is present in perspiration concentrations up to 10% in solutions, ointments, powders, 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 195 Chapter 6 Anti-infective Agents 195 and emulsions for topical administration. The preparation PHENOLS AND THEIR DERIVATIVES should never be applied to mucous membranes because it is Several phenols and their derivatives possess topical anti- a severe irritant. Undecylenic acid has been one of the fungal properties. Some of these, such as hexylresorcinols agents traditionally used for athlete’s foot (tinea pedis). and parachlorometaxylenol have been used for the treat- Cure rates are low, however. ment of tinea infections. Two phenolic compounds, clio- Triacetin quinol and haloprogin, are still official in the USP. A third Glyceryl triacetate (Enzactin, Fungacetin) is a colorless, oily agent, ciclopirox olamine, is not a phenol but has proper- liquid with a slight odor and a bitter taste. The compound is ties like those of phenols. All of these agents appear to in- soluble in water and miscible with alcohol and most organic terfere with cell membrane integrity and function in sus- solvents. ceptible fungi. The activity of triacetin is a result of the acetic acid re- leased by hydrolysis of the compound by esterases present in the skin. Acid release is a self-limiting process because the esterases are inhibited below pH 4. Haloprogin 3-Iodo-2-propynyl-2,4,5-trichlorophenyl ether (Halotex) crystallizes as white to pale yellow forms that are sparingly Salicylic Acid and Resorcinol soluble in water and very soluble in ethanol. It is an ethereal Salicylic acid is a strong aromatic acid (pKa 2.5) with both an- derivative of a phenol. Haloprogin is used as a 1% cream for tiseptic and keratolytic properties. It occurs as white, needle- the treatment of superficial tinea infections. like crystals or a fluffy crystalline powder, depending on how the compound was brought out of solution. Salicylic acid is only slightly soluble in water but is soluble in most organic solvents. The greater acidity of salicylic acid and its lower solubility in water compared with p-hydroxybenzoic acid are the consequence of intramolecular hydrogen bonding. Formulations of haloprogin should be protected from light because the compound is photosensitive. Haloprogin is available as a solution and a cream, both in a 1% concentra- tion. Haloprogin is probably not the first topical agent that should be recommended. Although the cure rates for topical Salicylic acid is used externally in ointments and solu- fungal infections are relatively high, they come at a high tions for its antifungal and keratolytic properties. By itself, price. The lesion typically worsens before it improves. salicylic acid is a poor antifungal agent. Inflammation and painful irritation are common. m-Hydroxyphenol (resorcinol) possesses antiseptic and Clioquinol keratolytic activity. It occurs as white, needlelike crystals 5-Chloro-7-iodo-8-quinolinol, 5-chloro8-hydroxy-7- and has a slightly sweet taste. Resorcinol is soluble in water, iodoquinoline, or iodochlorhydroxyquin (Vioform) occurs alcohols, and organic solvents. as a spongy, light-sensitive, yellowish white powder that is insoluble in water. Vioform was initially used as a substitute for iodoform in the belief that it released iodine in the tis- sues. It has been used as a powder for many skin conditions, such as atopic dermatitis, eczema, psoriasis, and impetigo. A 3% ointment or cream has been used vaginally as a treat- ment for Trichomonas vaginalis vaginitis. The best use for Vioform is in the topical treatment of fungal infections such Benzoic Acid as athlete’s foot and jock itch. A combination with hydro- Benzoic acid possesses appreciable antifungal effects, but it cortisone (Vioform HC) is also available. cannot penetrate the outer layer of the skin in infected areas. Therefore, benzoic acid when used as an antifungal agent must be admixed with a keratolytic agent. Suitable mixtures are benzoic acid and salicylic acid and benzoic acid and res- orcinol. An old preparation that is still in use is Whitfield’s Ointment, USP. This ointment contains benzoic acid, 6%, and salicylic acid, 6%, in a petrolatum base. The cure rates from preparations like these are low. 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 196 196 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry Figure 6.3 Mechanism of action of 5-fluorocytosine. Ciclopirox Olamine25 The mechanism of action of 5-fluorocytosine (5-FC) 6-Cyclohexyl-1-hydroxyl-4-methyl-2(1H)-pyridinone has been studied in detail and is presented in Figure 6.3. ethanolamine salt (Loprox) is a broad-spectrum antifungal The drug enters the fungal cell by active transport on agent intended only for topical use. It is active against der- ATPases that normally transport pyrimidines. Once inside matophytes as well as pathogenic yeasts (C. albicans) that the cell, 5-fluorocytosine is deaminated in a reaction cat- are causative agents for superficial fungal infections. alyzed by cytosine deaminase to yield 5-fluorouracil (5-FU). 5-Fluorouracil is the active metabolite of the drug. 5-Fluorouracil enters into pathways of both ribonucleotide and deoxyribonucleotide synthesis. The fluororibonu- cleotide triphosphates are incorporated into RNA, causing faulty RNA synthesis. This pathway causes cell death. In the deoxyribonucleotide series, 5-fluorodeoxyuridine monophosphate (F-dUMP) binds to 5,10-methylenete- trahydrofolic acid, interrupting the one-carbon pool sub- strate that feeds thymidylate synthesis. Hence, DNA syn- Ciclopirox is considered an agent of choice in the treat- thesis is blocked. ment of cutaneous candidiasis, tinea corporis, tinea cruris, Resistance to 5-FC is very common, and it occurs at tinea pedis, and tinea versicolor. It is a second-line agent for several levels. A main one is at the step in which the drug the treatment of onychomycosis (ringworm of the nails). is transported into the fungal cell. The transport system Loprox is formulated as a cream and a lotion, each contain- simply becomes impermeable to 5-FC. The cytosine deam- ing 1% of the water-soluble ethanolamine salt. Ciclopirox is inase step is another point at which resistance occurs, and believed to act on cell membranes of susceptible fungi at the UMP pyrophosphorylase reaction is a third point at low concentrations to block the transport of amino acids into which fungal cells can become resistant. Regardless of the cells. At higher concentrations, membrane integrity is which of these mechanisms operates, fungal resistance de- lost, and cellular constituents leak out. velops rapidly and completely when 5-FC is administered. After a few dosing intervals, the drug is essentially useless. Nucleoside Antifungals One strategy used to decrease resistance and to prolong the Flucytosine26 effect of 5-FC is to administer it with the polyene antibi- 5-Fluorocytosine, 5-FC, 4-amino-5-fluoro-2(1H)-pyrimidi- otic amphotericin B. The antibiotic creates holes in the none, 2-hydroxy-4-amino-5-fluoropyrimidine (Ancobon). fungal cell membrane, bypassing the transport step and al- 5-Fluorocytosine is an orally active antifungal agent with a lowing 5-FC to enter. Additionally, a lower dose of 5-FC very narrow spectrum of activity. It is indicated only for the can be used, preventing resistance by other mechanisms treatment of serious systemic infections caused by suscepti- for a longer period. ble strains of Candida and Cryptococcus spp. Antifungal Antibiotics27,28 The antifungal antibiotics make up an important group of antifungal agents. All of the antibiotics are marked by their complexity. There are two classes: the polyenes, which con- tain a large number of agents with only a few being useful, and griseofulvin (one member of the class). 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 197 Chapter 6 Anti-infective Agents 197 POLYENES Amphotericin B The isolation of amphotericin B (Fungizone) was reported Several structurally complex antifungal antibiotics have been in 1956 by Gold et al.29 The compound was purified from isolated from soil bacteria of the genus Streptomyces. The the fermentation beer of a soil culture of the actinomycete compounds are similar, in that they contain a system of con- Streptomyces nodosus, which was isolated in Venezuela. jugated double bonds in macrocyclic lactone rings. They dif- The first isolate from the streptomycete was a separable fer from the erythromycin-type structures (macrolides; see mixture of two compounds, designated amphotericins A and Chapter 8), in that they are larger and contain the conjugated B. In test cultures, compound B proved to be more active, -ene system of double bonds. Hence, they are called the poly- and this is the one used clinically.30 The structure and ab- ene antibiotics. The clinically useful polyenes fall into two solute stereochemistry are as shown. groupings on the basis of the size of the macrolide ring. The Amphotericin B is believed to interact with membrane 26-membered–ring polyenes, such as natamycin (pimaricin), sterols (ergosterol in fungi) to produce an aggregate that form one group, whereas the 38-membered macrocycles, forms a transmembrane channel. Intermolecular hydrogen such as amphotericin B and nystatin, form the other group. bonding interactions among hydroxyl, carboxyl, and amino Also common to the polyenes are (a) a series of hydroxyl groups stabilize the channel in its open form, destroying groups on the acid-derived portion of the ring and (b) a gly- symport activity and allowing the cytoplasmic contents to cosidically linked deoxyaminohexose called mycosamine.The leak out. The effect is similar with cholesterol. This explains number of double bonds in the macrocyclic ring differs also. the toxicity in human patients. As the name implies, ampho- Natamycin, the smallest macrocycle, is a pentaene; nystatin is tericin B is an amphoteric substance, with a primary amino a hexaene; and amphotericin B is a heptaene. group attached to the mycosamine ring and a carboxyl group The polyenes have no activity against bacteria, rickettsia, on the macrocycle. The compound forms deep yellow or viruses, but they are highly potent, broad-spectrum anti- crystals that are sparingly soluble in organic solvents but in- fungal agents. They do have activity against certain protozoa, soluble in water. Although amphotericin B forms salts with such as Leishmania spp. They are effective against patho- both acids and bases, the salts are only slightly soluble in genic yeasts, molds, and dermatophytes. Low concentrations water (⬃0.1 mg/mL) and, hence, cannot be used systemi- of the polyenes in vitro will inhibit Candida spp., cally. To create a parenteral dosage form, amphotericin B is Coccidioides immitis, Cryptococcus neoformans, H. capsu- stabilized as a buffered colloidal dispersion in micelles with latum, Blastomyces dermatitidis, Mucor mucedo, Aspergillus sodium deoxycholate.31 The barrel-like structure of the an- fumigatus, Cephalosporium spp., and Fusarium spp. tibiotic develops interactive forces with the micellar compo- The use of the polyenes for the treatment of systemic in- nents, creating a soluble dispersion. The preparation is light, fections is limited by the toxicities of the drugs, their low heat, salt, and detergent sensitive. water solubilities, and their poor chemical stabilities. Parenteral amphotericin B is indicated for the treatment Amphotericin B, the only polyene useful for the treatment of of severe, potentially life-threatening fungal infections, in- serious systemic infections, must be solubilized with a de- cluding disseminated forms of coccidioidomycosis and tergent. The other polyenes are indicated only as topical histoplasmosis, sporotrichosis, North American blastomy- agents for superficial fungal infections. cosis, cryptococcosis, mucormycosis, and aspergillosis. The mechanism of action of the polyenes has been stud- The usefulness of amphotericin B is limited by a high ied in some detail. Because of their three-dimensional shape, prevalence of adverse reactions. Nearly 80% of patients a barrel-like nonpolar structure capped by a polar group (the treated with amphotericin B develop nephrotoxicity. Fever, sugar), they penetrate the fungal cell membrane, acting as headache, anorexia, gastrointestinal distress, malaise, and “false membrane components,” and bind closely with ergos- muscle and joint pain are common. Pain at the site of injec- terol, causing membrane disruption, cessation of membrane tion and thrombophlebitis are frequent complications of enzyme activity, and loss of cellular constituents, especially intravenous administration. The drug must never be admin- potassium ions. In fact, the first observable in vitro reaction istered intramuscularly. The hemolytic activity of ampho- upon treating a fungal culture with amphotericin B is the loss tericin B may be a consequence of its ability to leach cho- of potassium ions. The drug is fungistatic at low concentra- lesterol from erythrocyte cell membranes. tions and fungicidal at high concentrations. This suggests For fungal infections of the central nervous system that at low concentrations, the polyenes bind to a membrane- (CNS) (e.g., cryptococcosis), amphotericin B is mixed with bound enzyme component, such as an ATPase. cerebrospinal fluid (CSF) that is obtained from a spinal tap. Amphotericin B 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 198 198 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry The solution of amphotericin B is then reinjected through suspension. The oral suspension is intended for the treat- the tap. For severe infections, this procedure may need to be ment of oral and pharyngeal candidiasis. The patient should repeated many times. swish the suspension in his or her mouth and swallow it. The Amphotericin B for injection is supplied as a sterile suspension has a very bad taste, so compliance may be a lyophilized cake or powder containing 50 mg of antibiotic problem. A slowly developing resistance to amphotericin B with 41 mg of sodium deoxycholate to be dispersed in has been described. This is believed to relate to alterations 10 mL of water. The infusion, providing 0.1 mg/mL, is pre- in the fungal cell membrane. pared by further dilution (1:50) with 5% dextrose for injec- Nystatin tion. Normal saline cannot be used because it will break the Nystatin (Mycostatin) is a polyene antibiotic that was first micelles. The suspension should be freshly prepared and isolated in 1951 from a strain of the actinomycete used within 24 hours. Even the powder should be refriger- Streptomyces noursei by Hazen and Brown.33 It occurs as a ated and protected from light. yellow to light tan powder. Nystatin is very slightly soluble Several sterile dosage forms32 with amphotericin B ad- in water and sparingly soluble in organic solvents. The com- mixed with a lipid carrier have been developed with the goal pound is unstable to moisture, heat, and light. of counteracting the dose-limiting toxicity of the drug fol- The aglycone portion of nystatin is called nystatinolide. lowing parenteral administration. These include ampho- It consists of a 38-membered macrolide lactone ring con- tericin B colloidal dispersion (Amphocil, Amphocyte), taining single tetraene and diene moieties separated by two which contains nearly equal parts of the drug and choles- methylene groups.34 The aglycone also contains eight hy- terol sulfate in a suspension of disklike particles; Abelcet, a droxyl groups, one carboxyl group, and the lactone ester 1:1 combination of amphotericin B with L-␣-dimyris- functionality. The entire compound is constructed by link- toylphosphatidylcholine (7 parts) and L-␣-dimyristoylphos- ing the aglycone to mycosamine. The complete structure of phatidylglycerol (3 parts) to create a suspension of ribbon- nystatin has been determined by chemical degradation and like sheets; and liposomal amphotericin B (AmBisome), a x-ray crystallography.35 small laminar vesicular preparation consisting of an approx- Nystatin is not absorbed systemically when adminis- imately 1:10 molar ratio of amphotericin B and lipid (hydro- tered by the oral route. It is nearly insoluble under all con- genated soy phosphatidyl choline, cholesterol, and dis- ditions. It is also too toxic to be administered parenterally. tearoylphosphatidylcholine in a 10:5:4 ratio) for an aqueous Hence, it is used only as a topical agent. Nystatin is a valu- suspension. able agent for the treatment of local and gastrointestinal The rationale behind these lipid preparations is simple: monilial infections caused by C. albicans and other amphotericin B should have a greater avidity for the lipid Candida species. For the treatment of cutaneous and mu- vehicle than for cholesterol in cell membranes. Hence, tox- cocutaneous candidiasis, it is supplied as a cream, an oint- icity should be reduced. Lipid-associated amphotericin B ment, and a powder. Vaginal tablets are available for the should be drawn into the reticuloendothelial system, con- control of vaginal candidiasis. Oral tablets and troches are centrating in the lymphatic tissues, spleen, liver, and lungs, used in the treatment of gastrointestinal and oral candidia- where infectious fungi tend to locate. Lipases elaborated sis. Combinations of nystatin with tetracycline can be used by the fungi and the host should release the drug from the to prevent monilial overgrowth caused by the destruction lipid carrier, making it available to bind ergosterol in fun- of bacterial microflora of the intestine during tetracycline gal cell membranes to exert its fungistatic and fungicidal therapy. activities. Although nystatin is a pure compound of known struc- Clinical use of each of the approved lipid preparations ture, its dosage is still expressed in terms of units. One mil- has shown reduced renal toxicity. Liposomal amphotericin ligram of nystatin contains not less than 2,000 USP units. B has been approved specifically for the treatment of pul- monary aspergillosis because of its demonstrated superior- Natamycin36,37 ity to the sodium deoxycholate-stabilized suspension. Natamycin (pimaricin; Natacyn) is a polyene antibiotic ob- Amphotericin B is also used topically to treat cutaneous tained from cultures of Streptomyces natalensis. and mucocutaneous mycoses caused by C. albicans. The The natamycin structure consists of a 26-membered lactone drug is supplied in various topical forms, including a 3% ring containing a tetraene chromophore, an ␣,␤-unsaturated cream, a 3% lotion, a 3% ointment, and a 100-mg/mL oral lactone carbonyl group, three hydroxyl groups, a carboxyl Nystatin 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 199 Chapter 6 Anti-infective Agents 199 group, a trans epoxide, and a glycosidically joined my- and Epidermophyton. After systemic absorption, griseoful- cosamine. Like the other polyene antibiotics, natamycin is vin is carried by the systemic circulation and capillary beds amphoteric. to the skin, nails, and hair follicles, where it concentrates in keratin precursor cells, which are gradually exfoliated and replaced by healthy tissue. Griseofulvin is a fungistatic agent, and as the new, healthy tissue develops, the drug pre- vents reinfection. Treatment must be continued until all of the infected tissue has been exfoliated, because old tissues will still support and harbor fungal growth. Therapy in slow- growing tissues, such as the nails, must be continued for several months. Compliance with the drug regimen is mandatory. In some cases, such as with the nails, it is possi- ble to observe new, healthy tissue growing in to replace the infected tissue. Griseofulvin neither possesses antibacterial activity nor is effective against P. obiculare, the organism that causes tinea versicolor. The mechanism action of the smaller polyenes differs from Few adverse effects have been reported for griseofulvin. that of amphotericin B and nystatin. The 26-membered–ring The most common ones are allergic reactions such as rash polyenes cause both potassium ion leakage and cell lysis at and urticaria, gastrointestinal upset, headache, dizziness, the same concentration, whereas the 38-membered–ring poly- and insomnia. enes cause potassium leakage at low, fungistatic concentra- The oral bioavailability of griseofulvin is very poor. The tions and cell lysis at high, fungicidal concentrations. The compound is highly lipophilic with low water solubility. smaller polyenes are fungistatic and fungicidal within the The most successful attempts at improving absorption have same concentration range. centered on creating micronized (ultramicrosized, micro- Natamycin possesses in vitro activity against several sized) griseofulvin. Reducing the particle size, in theory, yeasts and filamentous fungi, including Candida, should improve dissolution in the stomach and absorption. Aspergillus, Cephalosporium, Penicillium, and Fusarium The efficiency of gastric absorption of griseofulvin ultrami- spp. The drug is supplied as a 5% ophthalmic suspension in- crosized versus the microsized form is about 1.5, allowing a tended for the treatment of fungal conjunctivitis, blepharitis, dosage reduction of one third. Several structural derivatives and keratitis. have been synthesized, but they have failed to improve ab- sorption. Perhaps the best advice that the pharmacist can Other Antifungal Antibiotics give a patient who is about to use griseofulvin is to take the Griseofulvin drug with a fatty meal, as with salad dressing. Griseofulvin (Grisactin, Gris-PEG, Grifulvin) was first re- Griseofulvin is a mitotic spindle poison.39,40 In vitro, it ported in 1939 by Oxford et al.38 as an antibiotic obtained rapidly arrests cell division in metaphase. It causes a rapid, from the fungus Penicillium griseofulvum. It was isolated reversible dissolution of the mitotic spindle apparatus, prob- originally as a “curling factor” in plants. Application of ex- ably by binding with the tubulin dimer that is required for tracts containing the antibiotic to fungus-infected leaf parts microtubule assembly. The selective toxicity to fungi is caused the leaf to curl up. The drug has been used for many probably because of the propensity of the drug to concen- years for its antifungal action in plants and animals. In 1959, trate in tissues rich in keratin, where dermatophytes typi- griseofulvin was introduced into human medicine for the cally establish infections. treatment of tinea infections by the systemic route. Allylamines and Related Compounds The allylamine class of antifungal agents was discovered as a result of random screening of a chemical inventory for compounds with antifungal activity. Structure–activity stud- ies in the series subsequently led to the discovery of com- pounds with enhanced potency and potential oral activity, such as terbinafine.41,42 Investigation of the mechanism of action of the allylamines demonstrated that the compounds Griseofulvin is an example of a rare structure in nature, a interfere with an early step in ergosterol biosynthesis, spiro compound. The structure of griseofulvin was deter- namely, the epoxidation of squalene catalyzed by squalene mined by Grove et al.39 to be 7-chloro-2,4,6-trimethoxy- epoxidase. Squalene epoxidase43 forms an epoxide at the 6,␤-methylspiro[benzofuran-2(3H)-1-cyclohexene]- C2–C3 position of squalene (Fig. 6.4). Opening of the epox- 3,4-dione. The compound is a white, bitter, heat-stable ide under acid catalysis yields a carbocation that initiates the powder or crystalline solid that is sparingly soluble in water “squalene zipper” reaction that forms the steroid nucleus. but soluble in alcohol and other nonpolar solvents. It is very Inhibition of squalene epoxidase shuts down the biosynthe- stable when dry. sis of ergosterol and causes an accumulation of squalene, Griseofulvin has been used for a long time for the sys- which destabilizes the fungal cell membrane. The allyl- temically delivered treatment of refractory ringworm infec- amines exert a fungicidal action against dermatophytes and tions of the body, hair, nails, and feet caused by species of other filamentous fungi, but their action against pathogenic dermatophytic fungi including Trichophyton, Microsporum, yeasts, such as Candida spp., is largely fungistatic. 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 200 200 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry Figure 6.4 Squalene epoxidase reaction. Although mammalian squalene epoxidase is weakly inhib- ited by the allylamines, cholesterol biosynthesis does not ap- pear to be altered. Two allylamines, naftifine and terbinafine, have been ap- proved as topical agents for the treatment of tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton Tolnaftate floccosum, respectively. The topical agent tolnaftate, al- O,2-Naphthyl m,N-dimethylthiocarbanilate (Tinactin, though not an allylamine, inhibits squalene epoxidase and Aftate, NP-27) is a white crystalline solid that is insoluble in has a spectrum of activity similar to that of the allylamines. water, sparingly soluble in alcohol, and soluble in most or- Hence, tolnaftate is classified with the allylamines. The al- ganic solvents. The compound, a thioester of ␤-naphthol, is lylamines are weak bases that form hydrochloride salts that fungicidal against dermatophytes, such as Trichophyton, are slightly soluble in water. Microsporum, and Epidermophyton spp., that cause superfi- Naftifine Hydrochloride cial tinea infections. Tolnaftate is available in a concentra- N-Methyl-N-(3-phenyl2-propenyl)-1-naphthalen- tion of 1% in creams, powders, aerosols, gels, and solutions emethanamine hydrochloride (Naftin) is a white crys- for the treatment of ringworm, jock itch, and athlete’s foot. talline powder that is soluble in polar solvents such as Tolnaftate has been shown to act as an inhibitor of squalene ethanol and methylene chloride. It is supplied in a 1% con- epoxidase44 in susceptible fungi, so it is classified with the centration in a cream and in a gel for the topical treatment allylamine antimycotics. Tolnaftate is formulated into prepa- of ringworm, athlete’s foot, and jock itch. Although unap- rations intended to be used with artificial fingernails to coun- proved for these uses, naftifine has shown efficacy for teract the increased chance of ringworm of the nail beds. treatment of ringworm of the beard, ringworm of the scalp, and tinea versicolor. Azole Antifungal Agents The azoles represent a class of synthetic antifungal agents that possess a unique mechanism of action. With these Terbinafine Hydrochloride drugs, one can achieve selectivity for the infecting fungus (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphtha- over the host. Depending on the azole drug used, one can lene-methanamine hydrochloride (Lamisil) is an off-white treat infections ranging from simple dermatophytoses to crystalline material that is soluble in polar organic solvents life-threatening, deep systemic fungal infections. Research such as methanol, ethanol, and methylene chloride but is currently under way in the United States is aimed at devel- only slightly soluble in water. The highly lipophilic free oping more potent azoles and compounds that penetrate the base is insoluble in water. Terbinafine hydrochloride is blood-brain barrier more effectively. The first members of available in a 1% cream for topical administration for the the class were highly substituted imidazoles, such as clotri- treatment of tinea pedis, tinea corporis, and tinea cruris. mazole and miconazole. Structure–activity studies revealed Terbinafine is more potent than naftifine and has also that the imidazole ring could be replaced with a bioisosteric demonstrated oral activity against onychomycosis (ring- 1,2,4-triazole ring without adversely affecting the antifungal worm of the nails). It has not been approved in the United properties of the molecule. Hence, the more generic term States for oral administration. azoles refers to this class of antifungal agents. 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 201 Chapter 6 Anti-infective Agents 201 ANTIFUNGAL SPECTRUM high in vitro concentrations (micromolar), the azoles are fun- gicidal; at low in vitro concentrations (nanomolar), they are The azoles tend to be effective against most fungi that cause fungistatic. The fungicidal effect is clearly associated with superficial infections of the skin and mucous membranes, damage to the cell membrane, with the loss of essential cellu- including the dermatophytes such as Trichophyton, lar components such as potassium ions and amino acids. The Epidermophyton, and Microsporum spp. and yeasts such as fungistatic effect of the azoles at low concentration has been C. albicans. On the other hand, they also exhibit activity associated with inhibition of membrane-bound enzymes. A against yeasts that cause systemic infections, including cytochrome P450-class enzyme, lanosterol 14␣-demethylase, C. immitis, C. neoformans, Paracoccidioides brasiliensis, is the likely target for the azoles.46 P450 possesses a heme Petriellidium boydii, B. dermatitidis, and H. capsulatum. moiety as part of its structure (Fig. 6.5), and the basic electron MECHANISM OF ACTION pairs of the azole rings can occupy a binding site on P450, preventing the enzyme from turning over. The function of The effects of the azoles on fungal biochemistry have been lanosterol 14␣-demethylase is to oxidatively remove a methyl studied extensively, but there is still much to be learned.45 At group from lanosterol during ergosterol biosynthesis. Figure 6.5 The inhibitory action of azole antifungal agents on the lanosterol 14-␣- demethylase reaction. 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 202 202 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry When demethylation is inhibited, the 14␣-sterol accumu- Clotrimazole is available as a solution in polyethylene lates in the membrane, causing destabilization. As this hap- glycol 400, a lotion, and a cream in a concentration of 1%. pens, repair mechanisms, such as chitin synthesis, are initi- These are all indicated for the treatment of tinea pedis, tinea ated to patch the damage. This degrades membrane function cruris, tinea capitis, tinea versicolor, or cutaneous candidia- further. Lanosterol 14␣-demethylase is also required for sis. A 1% vaginal cream and tablets of 100 mg and 500 mg mammalian biosynthesis of cholesterol, and the azoles are are available for vulvovaginal candidiasis. Clotrimazole is known to inhibit cholesterol biosynthesis.47 In general, extremely stable, with a shelf life of more than 5 years. higher concentrations of the azoles are needed to inhibit the mammalian enzyme. This provides selectivity for antifungal action. The 1,2,4-triazoles appear to cause a lower incidence of endocrine effects and hepatotoxicity than the correspon- ding imidazoles, possibly because of a lower affinity for the mammalian cytochrome P450 enzymes involved.48 The pri- mary mode of resistance to the triazoles and imidazoles in C. albicans is the development of mutations in ERG 11, the gene coding for C14-␣-sterol demethylase. These mutations appear to protect heme in the enzyme pocket from binding Although clotrimazole is effective against various patho- to azole but allow access of the natural substrate of the en- genic yeasts and is reasonably well absorbed orally, it zyme, lanosterol. Cross-resistance is conferred to all azoles. causes severe gastrointestinal disturbances. It is also exten- Increased azole efflux by the ATP-binding cassette (ABC-1, sively protein bound and, hence, is not considered optimally which normally transports cholesterol) and major facilitator bioavailable. Clotrimazole is not considered suitable for the superfamily transporters can add to fluconazole resistance in treatment of systemic infections. C. albicans and C. glabrata. Increased production of C14- Econazole Nitrate ␣-sterol demethylase could be another cause of resistance. 1-[2-[(4-Chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)- ethyl]-1H-imidazole (Spectazole) is a white crystalline ni- STRUCTURE–ACTIVITY RELATIONSHIPS tric acid salt of econazole. It is only slightly soluble in water The basic structural requirement for members of the azole and most organic solvents. class is a weakly basic imidazole or 1,2,4-triazole ring (pKa of 6.5–6.8) bonded by a nitrogen–carbon linkage to the rest of the structure. At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of molecular oxygen and prevent oxida- tion of steroidal substrates by the enzyme. The most potent antifungal azoles possess two or three aromatic rings, at least one of which is halogen substituted (e.g., 2,4- dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl), and other nonpolar functional groups. Only 2, and/or 2,4 substi- tution yields effective azole compounds. The halogen atom that yields the most potent compounds is fluorine, although Econazole is used as a 1% cream for the topical treatment functional groups such as sulfonic acids have been shown to of local tinea infections and cutaneous candidiasis. do the same. Substitution at other positions of the ring yields Butoconazole Nitrate inactive compounds. Presumably, the large nonpolar portion 1-[4-(4-Chlorophenyl)-2-[(2,6-dichlorophenyl)-thio]butyl]- of these molecules mimics the nonpolar steroidal part of the 1H-imidazole (Femstat) is an extremely broad-spectrum an- substrate for lanosterol 14␣-demethylase, lanosterol, in tifungal drug that is specifically effective against C. albi- shape and size. cans. It is supplied as a vaginal cream containing 2% of the The nonpolar functionality confers high lipophilicity to salt. It is intended for the treatment of vaginal candidiasis. the antifungal azoles. The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. Fluconazole, which possesses two polar triazole moieties, is an exception, in that it is sufficiently water solu- ble to be injected intravenously as a solution of the free base. PRODUCTS Clotrimazole 1-(o-Chloro-␣,␣-diphenylbenzyl)imidazole (Lotrimin, Gyne- Lotrimin, Mycelex) is a broad-spectrum antifungal drug that is used topically for the treatment of tinea infections and can- Sulconazole Nitrate didiasis. It occurs as a white crystalline solid that is sparingly 1-[2,4-Dichloro-␤-[p-chlorobenzyl)thio]phenethyl]imida- soluble in water but soluble in alcohol and most organic sol- zole mononitrate (Exelderm) is the white crystalline nitric vents. It is a weak base that can be solubilized by dilute min- acid salt of sulconazole. It is sparingly soluble in water but eral acids. soluble in ethanol. The salt is used in a solution and a cream 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 203 Chapter 6 Anti-infective Agents 203 in 1% concentration for the treatment of local tinea infec- The free base is available in an injectable form, solubi- tions, such as jock itch, athlete’s foot, and ringworm. lized with polyethylene glycol and castor oil, and intended for the treatment of serious systemic fungal infections, such as candidiasis, coccidioidomycosis, cryptococcosis, petriel- lidiosis, and paracoccidioidomycosis. It may also be used for the treatment of chronic mucocutaneous candidiasis. Although serious toxic effects from the systemic administra- tion of miconazole are comparatively rare, throm- bophlebitis, pruritus, fever, and gastrointestinal upset are relatively common. Miconazole nitrate is supplied in various dosage forms (cream, lotion, powder, and spray) for the treatment of tinea infections and cutaneous candidiasis. Vaginal creams and Oxiconazole Nitrate suppositories are also available for the treatment of vaginal (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone- candidiasis. A concentration of 2% of the salt is used in O-[2,4-dichlorophenyl)methyl]oxime mononitrate (Oxistat) most topical preparations. is a white crystalline nitric acid salt. It is used in cream and Ketoconazole lotion dosage forms in 1% concentration for the treatment of 1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2(1H-imidazole-1- tinea pedis, tinea corporis, and tinea capitis. ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine (Nizoral) is a broad-spectrum imidazole antifungal agent that is administered orally for the treatment of systemic fun- gal infections. It is a weakly basic compound that occurs as a white crystalline solid that is very slightly soluble in water. Tioconazole 1-[2-[(2-chloro-3-thienyl)methoxy]2-(2,4-dichlorophenyl)- ethyl]-1H-imidazole (Vagistat) is used for the treatment of vulvovaginal candidiasis. A vaginal ointment containing The oral bioavailability of ketoconazole depends on an 6.5% of the free base is available. Tioconazole is more ef- acidic pH for dissolution and absorption. Antacids and drugs fective against Torulopsis glabrata than are other azoles. such as H2-histamine antagonists and anticholinergics that inhibit gastric secretion interfere with its oral absorption. Ketoconazole is extensively metabolized to inactive metabolites, and the primary route of excretion is enterohe- patic. It is estimated to be 95% to 99% bound to protein in the plasma. Hepatotoxicity, primarily of the hepatocellular type, is the most serious adverse effect of ketoconazole. Ketoconazole is known to inhibit cholesterol biosynthesis,47 suggesting that lanosterol 14␣-demethylase is inhibited in mammals as well as in fungi. High doses have also been re- Miconazole Nitrate ported to lower testosterone and corticosterone levels, re- 1-[2-(2,4-Dichlorophenyl)-2-[2,4-dichlorophenyl]- flecting the inhibition of cytochrome P450-requiring en- methoxy]ethyl]-1H-imidazole mononitrate (Monistat, zymes involved in human steroid hormone biosynthesis.48 Micatin) is a weak base with a pKa of 6.65. The nitric acid Cytochrome P450 oxidases responsible for the metabolism salt occurs as white crystals that are sparingly soluble in of various drugs may also be inhibited by ketoconazole to water and most organic solvents. cause enhanced effects. Thus, ketoconazole causes clini- cally significant increases in plasma concentrations of cy- closporine, phenytoin, and terfenadine. It may also enhance responses to sulfonylurea hypoglycemic and coumarin anti- coagulant drugs. Ketoconazole is a racemic compound, consisting of the cis-2S,4R and cis-2R,4S isomers. An investigation of the rel- ative potencies of the four possible diastereomers of keto- conazole against rat lanosterol 14␣-demethylase49 indicated that the 2S,4R isomer was 2.5 times more active than its 2R,4S enantiomer. The trans-isomers, 2S,4S and 2R,4R, are much less active.49 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 204 204 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry Ketoconazole is recommended for the treatment of the reduce stomach acidity, reduce its gastrointestinal absorp- following systemic fungal infections: candidiasis (including tion. Food greatly enhances the absorption of itraconazole, oral thrush and the chronic mucocutaneous form), coccid- nearly doubling its oral bioavailability. The drug is avidly ioidomycosis, blastomycosis, histoplasmosis, chromomyco- bound to plasma proteins (nearly 99% at clinically effective sis, and paracoccidioidomycosis. It is also used orally to concentrations) and extensively metabolized in the liver. treat severe refractory cutaneous dermatophytic infections Only one of the numerous metabolites, namely 1-hydroxyi- not responsive to topical therapy or oral griseofulvin. The traconazole, has significant antifungal activity. Virtually antifungal actions of ketoconazole and the polyene antibi- none of the unchanged drug is excreted in the urine. Thus, otic amphotericin B are reported to antagonize each other. the dosage need not be adjusted in patients with renal im- Ketoconazole is also used topically in a 2% concentra- pairment. The terminal elimination half-life of itraconazole tion in a cream and in a shampoo for the management of cu- ranges from 24 to 40 hours. taneous candidiasis and tinea infections. The primary indications for itraconazole are for the treat- ment of systemic fungal infections including blastomycosis, Terconazole histoplasmosis (including patients infected with human im- cis-1-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl- munodeficiency virus [HIV]), nonmeningeal coccid- methyl)-1,3-dioxolan-4-yl)methoxy]phenyl]-4-(1 ioidomycosis, paracoccidioidomycosis, and sporotrichosis. methylethyl)piperazine (Terazol), or terconazole, is a tria- It may also be effective in the treatment of pergellosis, dis- zole derivative that is used exclusively for the control of seminated and deep organ candidiasis, coccidioidal menin- vulvovaginal moniliasis caused by C. albicans and other gitis, and cryptococcosis. Candida species. It is available in creams containing 0.4% In general, itraconazole is more effective and better tol- and 0.8% of the free base intended for 7-day and 3-day treat- erated than is ketoconazole. Unlike ketoconazole, it is not ment periods, respectively. Suppositories containing 80 mg hepatotoxic and does not cause adrenal or testicular suppres- of the free base are also available. sion in recommended therapeutic doses.14 Nonetheless, itra- conazole can inhibit cytochrome P450 oxidases involved in drug and xenobiotic metabolism and is known to increase plasma levels of the antihistaminic drugs terfenadine and astemizole. Fluconazole ␣-(2,4-Difluorophenyl)-␣-(1H-1,2,4-triazol-1-ylmethyl)- 1H-1,2,4-triazole-1-ethanol or 2,4-difluoro-␣,␣-bis(1H-1, 2,4-triazol-1-ylmethyl)benzyl alcohol (Diflucan) is a water- soluble bis-triazole with broad-spectrum antifungal proper- ties that is suitable for both oral and intravenous administra- Itraconazole tion as the free base. Intravenous solutions of fluconazole 4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-1H-1,2,4-triazol-1- contain 2 mg of the free base in 1 mL of isotonic sodium ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piper- chloride or 5% dextrose vehicle. azinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4- triazol-3-one (Sporanox) is a unique member of the azole class that contains two triazole moieties in its structure, a weakly basic 1,2,4-triazole and a nonbasic 1,2,4-triazol- 3-one. Itraconazole is an orally active, broad-spectrum antifun- gal agent that has become an important alternative to keto- conazole. An acidic environment is required for optimum solubilization and oral absorption of itraconazole. Drugs such as H2-histamine antagonists and antacids, which Itraconazole 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 205 Chapter 6 Anti-infective Agents 205 The oral bioavailability of fluconazole, following admin- istration of either tablet or oral suspension dosage forms, is excellent. Apparently, the presence of two weakly basic tri- azole rings in the molecule confers sufficient aqueous solu- bility to balance the lipophilicity of the 2,4-difluorophenyl group. The oral absorption of fluconazole, in contrast to the oral absorption of ketoconazole or itraconazole, is not af- fected by alteration in gastrointestinal acidity or the pres- ence of food. Fluconazole has a relatively long elimination half-life, ranging from 27 to 34 hours. It penetrates well into all body cavities, including the CSF. Plasma protein binding of fluconazole is less than 10%; the drug is efficiently re- Unlike fluconazole, voriconazole has potent activity moved from the blood by hemodialysis. Fluconazole expe- against a broad variety of fungi, including the clinically im- riences little or no hepatic metabolism and is excreted sub- portant pathogens. Several publications have substantiated stantially unchanged in the urine. A small amount of the use of voriconazole against some of the newer and rarer unchanged fluconazole (⬃10%) is excreted in the feces. fungal pathogens. Voriconazole is more potent than itra- Side effects of fluconazole are largely confined to minor conazole against Aspergillus spp. and is comparable to gastrointestinal symptoms. Inhibition of cytochrome P450 posaconazole,50 another azole that is in clinical trials, in its oxidases by fluconazole can give rise to clinically signifi- activity against C. albicans. In general, Candida spp. that cant interactions involving increased plasma levels of cy- are less susceptible to fluconazole possess higher MICs to closporine, phenytoin, and the oral hypoglycemic drugs voriconazole. The in vitro activity of posaconazole appears (tolbutamide, glipizide, and glyburide). Fluconazole does to be similar to that of voriconazole. Posaconazole is now in not appear to interfere with corticosteroid or androgen phase III clinical trials, and evidence of the efficacy of biosynthesis in dosages used to treat systemic fungal posaconazole against various fungal models, especially the infections. rarer ones, continues to accumulate. Posaconazole exhibits Fluconazole is recommended for the treatment and high oral bioavailability, but its low water solubility makes prophylaxis of disseminated and deep organ candidiasis. its formulation into an intravenous solution impossible. It is also used to control esophageal and oropharyngeal A search for potential prodrug forms of posaconazole has candidiasis. Because of its efficient penetration into CSF, yielded a possible candidate, SCH 59884. The compound is fluconazole is an agent of choice for the treatment of inactive in vitro but is dephosphorylated in vivo to yield the cryptococcal meningitis and for prophylaxis against active 4-hydroxybutyrate ester. This compound is hy- cryptococcosis in AIDS patients. Although fluconazole drolyzed to the parent compound in the serum. Posaconazole is generally less effective than either ketoconazole or undergoes extensive enterohepatic recycling, and most of the itraconazole against nonmeningeal coccidioidomycosis, it dose is eliminated in the bile and feces. is preferred therapy for coccidioidal meningitis. Syn2869 is a novel broad-spectrum compound that con- Fluconazole lends itself to one-dose therapies for vaginal tains the piperazine-phenyl-triazolone side chain common candidiasis. to itraconazole and posaconazole, and it displays potency and an antifungal spectrum similar to those of the latter. NEWER ANTIFUNGAL STRATEGIES Syn2869 demonstrates better activity than itraconazole in animal models of C. albicans, C. glabrata, and C. neofor- A newer azole is voriconazole.50 mans. The oral bioavailability (F) is 60%, and higher SCH 59884 Syn2869 0179-0241_17865_Ch06.qxd 12/8/09 10:55 PM Page 206 206 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry tissue-to-serum ratios than those found for itraconazole demonstrate good in vitro and in vivo activity against were claimed to contribute to the greater efficacy of the Candida spp. and C. neoformans clinical isolates. compound in a model of invasive pulmonary aspergillosis. Syn2869 also demonstrates considerable activity against the common mold pathogens. SYNTHETIC ANTIBACTERIAL AGENTS ECHINOCANADINS AND PNEUMOCANADINS Several organic compounds obtained by chemical synthesis on the basis of model compounds have useful antibacterial Echinocanadins51 and the closely related pneumocanadins52 activity for the treatment of local, systemic, and/or urinary are natural products that were discovered in the 1970s. tract infections. Some chemical classes of synthetic antibac- They act as noncompetitive inhibitors of (1,3)-␤-d-glucan terial agents include the sulfonamides, certain nitrohetero- synthase,53 an enzyme complex that forms stabilizing glucan cyclic compounds (e.g., nitrofurans, metronidazole), and the polymers in the fungal cell wall. Three water-soluble deriva- quinolones. Some antibacterial agents that fail to achieve tives of the echinocanadins and pneumocanadins are in end- adequate concentrations in the plasma or tissues for the stage clinical development but have not yet been marketed. treatment of systemic infections following oral or parenteral LY 303366 is a pentyloxyterphenyl side chain derivative administration are concentrated in the urine, where they of echinocanadin B that was discovered at Eli Lilly. It was can be effective for eradicating urinary tract infections. licensed for parenteral use in 2000. Studies have shown that Nitrofurantoin (a nitrofuran), nalidixic acid (a quinolone), the MICs of LY 303366 against Candida spp. range from and methenamine are examples of such urinary tract anti- 0.08 to 5.12 ␮g/mL, and similar activity was obtained infectives. agai