antifungal activity of the polyenes can be reduced by the addition of sterols or in the presence of sterol-complexing agents.

Very few polyenes are used clinically, and two of the most important are nystatin and amphotericin B ((11.121) R=H). They show activity against yeasts and fungi but not bacteria. The therapeutic usefulness of the polyenes as a group is limited by their solubility and stability and especially by their toxicity. Polyene methyl esters have been synthesized and this is a definite advance. For example, amphotericin B methyl ester ((11.122) R=CH3) is water-soluble and can be administered intravenously as a solution, whereas amphotericin B is insoluble in water (possibly due to zwitterion formation) and is formulated as a colloidal form with sodium deoxycholate. The two forms have equal antifungal activity, but much higher peak serum levels are obtained with the ester which is also considerably less toxic. However, neurological effects have been noted with the methyl ester. More recently, an ascorbate salt has been described, which is water-soluble, of similar activity and less toxic.

A new approach has been to deliver amphotericn B in a liposomal formulation, which is thought to reduce toxicity.

Future design of polyenic antibiotics might be related to an improved understanding of the nature of their interaction with sterols. In this context, it is pertinent to record the desired property of increased interaction between polyene and fungal membrane ergosterol and decreased interaction between polyene and mammalian membrane cholesterol. Filipen has a high affinity for fungal membrane sterol and for cholesterol and thus has cytotoxic and haemolytic properties, rendering it too toxic for clinical use.

(11.121) Etmphoiericin B: R = H (11.122) amphotericin B iricihyl tster: R = CH

11.7.2 Imidazole derivatives

The antifungal imidazoles comprise a large and diverse group of compounds. Some have antibacterial properties (e.g. metronidazole (11.123) which is of importance in treating anaerobic bacterial infections), others are antihelminthic agents (such as mebendazole) and some, notably clotrimazole (11.124), miconazole (11.125), ketoconazole (11.126) and econazole (11.127) are potent antifungal agents. Two newer agents are fluconazole (11.128) and itraconazole (11.129) with less potential for toxicity than the other agents. None of these agents is fungicidal in action, which may be regarded as a drawback,



(11.129) itraconazole though no clinical disadvantage has been observed. The imidazoles have resulted from the synthesis and testing of many hundreds of derivatives rather than from any planned programme of designing new agents based on a knowledge of the structure and biosynthesis processes of the fungal cell.

The synthetic imidazoles are generally hydrophobic, and their use is often limited by toxicity. They interact with unsaturated fatty acids in the fungal cell membrane, although the exact mechanism of action is still unclear, because mammalian cells also contain unsaturated fatty acids. Selective toxicity probably results from their selective inhibition of the demethylation of the 14a-lanosterol in ergosterol biosynthesis.

Griseofulvin (11.130) was isolated from the mould Penicillium griseofulvum in 1939, but because of its lack of antibacterial activity was not then investigated further. Several years later, it was found to be a potent antifungal antibiotic, albeit with a fungistatic rather than a fungicidal action, with significant activity against dermatophytes (Trichophyton, Epidermophyton and Microsporum spp.) but not against Cryptococcus, Aspergillus or Candida spp. or against bacteria.

Successful antifungal therapy of certain conditions requires adequate penetration of nail keratin. Orally administered griseofulvin is deposited in the deeper layers of the skin, in hair and in keratin of the nails, and is used in the treatment of fungal infections of the skin, hair and nails caused by susceptible organisms.

Griseofulvin is not totally absorbed when given orally, and one method of increasing absorption is to reduce the particle size of the drug.

11.7.3 Griseofulvin

CHjO (11.130) griseofuLviu

CHjO (11.130) griseofuLviu

11.7.4 Flucytosine

Flucytosine (5-fluorocytosine (11.131)) has a relatively narrow spectrum of activity, with yeasts (including Candida and Cryptococcus) being most sensitive. It acts as a competitive antimetabolite for uracil in the synthesis of yeast RNA and it also interferes with thymidylate synthetase, thus affecting DNA synthesis. Once inside the fungal cell, flucytosine is deaminated to 5-fluorouracil (11.132) which cannot itself be used because of (a) its poor penetration into fungi, and (b) its toxicity to human cells. This intracellular deamination is important because the 5-fluorouracil replaces uracil in the fungal RNA, thereby inhibiting RNA synthesis. Furthermore, Candida albicans converts flucytosine to 5-fluorodeoxyuridine monophosphate (FUdRMP)) which inhibits thymidylate synthetase and thus DNA synthesis.


(11.131) flucytosine

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