Amphotericin B is the main polyene macrolide antibiotic due to its high antifungal activity and broad spectrum of activity. Recently the range of medical application of amphotericin B has expanded in connection with its use in combination with synthetic antifungal drugs for therapy of fungal infections, and also the discovery of its antiviral, antitumor and antileishmanial activity. Amphotericin B is especially important for treating fungal diseases that complicate AIDS. Nevertheless, the high toxicity (in particular, nephrotoxicity) of amphotericin B, the low absorption from the gastrointestinal tract and poor penetration into cerebrospinal fluid, a whole series of side reactions, and the reduced sensitivity to it of pathogenic fungal microorganisms have stimulated vigorous searches for different derivatives of this heptaene macrolide antibiotic with improved medical and biological properties.
We demonstrated that interaction of amphotericin B with various dialkyl(diaryl)phosphites in the presence of organic base resulted in the corresponding dialkyl-(diaryl)amidophosphonate derivatives. The biological testes showed that acute toxicity (LD50) of these derivatives was four times lower than that of the starting antibiotic, and the LD50 values were of 950 to 980 mg/kg (mice, intraperitoneal). The synthesized derivatives of amphotericin B possessed high antifungal activity against various pathogenic fungi, and especially against six test cultures of yeast fungi of the genus Candida. It was found that the minimal fungistatic concentration (MFC) in the relation of test cultures of yeast fungi of the genus Candida varied from 0.10 to 6.25 (μg/mL).
