Polyene antifungal agents

Hoeprich and Huston [117] assessed the stability of miconazole and three other antifungal agents under conditions encountered in bioassay and susceptibility testing in vitro. Although the amphotericins were labile as compared with other drugs, tests should be reliable with all four drugs in view of the rapid action of the polyenes and the relatively slow action of miconazole and 5-fluorocytosines. 

Mechanism of Action A polyene antifungal agent that increases cell membrane permeability in susceptible fungi. Therapeutic Effect Fungicidal. 

The complex polyene macrolide antibiotics are clinically effective as antifungal agents. Scott Rychnovsky of the University of California at Irvine has reported (Angew. Chem. hit. Ed. 2004,43, 2822) the first synthesis of rimocidinolide methyl ester 4, the aglycone of rimocidin 1. The key step in the synthesis is the condensation of the aldehyde 2 with the phosphonate 3, leading to 4. 

Natamycin is another polyene antibiotic effective against dermatophytes. The name originally proposed for the compound was pimaricin, which has been used in some of the earlier literature studies and reports. It has been used as topical therapeutic in animals and humans for over 30 years, and it is also used as an antifungal agent in food processing. 

Macrolides. Antibiotics in the macrolide group are macrocyclic lactones that can be further classified into two main subgroups (I) polyene macrolides that are antifungal agents and include compounds like nystatin and amphotericin B and (2) antibacterial antibiotics represented by erythromycin and tylosin. A number of other subfamilies of antibacterial and antifungal antibiotics fall into the broad category of macrolides,... 

One compound that has been associated with distal tubular injury is amphotericin B, a polyene antifungal agent used in the treatment of systemic mycoses caused by opportunistic fungi. Clinical utility of amphotericin B is limited by its nephrotoxicity, characterized functionally by polyuria resistant to antidiuretic hormone administration, hyposthenuria, hypokalemia, and mild renal tubular acidosis. 

A rabbit model for Candida albicans compared the efficacy of topical amphotericin B with four other antifungal agents. Amphotericin B and 5% natamycin were the most effective, 1% miconazole and 1% flucytosine were effective but inferior to the polyenes, and 1% ketoconazole was not effective (O Day et al.). 

Fig. 4.3 Structures of polyene (amphotericin B) and azole (itraconazole, fluconazole, miconazole and ketoconazole) antifungal agents.

Fig. 4.4 Modes of action of polyene and azole antifungal agents showing sites of action.

Disruption of cell membrane function Azole and polyene antifungal agents... 

Although the heptaene polyene SPK-843 (41, Figure 8) was in phase II clinical trials as an antifungal agent, it was reported by Kaken as being discontinued in late 2007. Even close to 70 years after the introduction of amphotericin, the basic polyene scaffold is still being used as the basis for new agents, in spite of the synthetic azoles in current use. 

Antifungal Agents. The chemistry, mechanism of action, and clinical utility of the antifungal polyene antibiotics was discussed in Chapter 2. 

Natamycin is an ophthalmic antifungal agent, which binds to fungal cell membrane, altering membrane permeability and depleting essential cellular constituents. A polyene mac-rolide antibiotic (instill 1 drop of 5% solution in conjunctival sac), natamycin is used in conjunctivitis, keratitis, and blepharitis caused by susceptible fungi. 

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