Hydrophosphoryl Derivatives of Tetraene Macrolide Antibiotic Tetramycin B: Design, Synthesis, Antifungal Activity and Development of Intellectual Computer System

Antifungal antibiotic tetramycin B discovered by German researchers is a member of tetraene macrolide antibiotics family. Tetramycin B was prepared via the microbiological synthesis by Streptomyces noursei as the producer; its structure as well as physical, chemical, and medical and biological properties have been studied in detail. However, in contrast to tetraene macrolide antibiotics nystatin and pimaricin, tetramycin B has not been applied in the mycological therapy due to the high toxicity. Chemical modification of polyene macrolide antibiotics is known to afford less toxic derivatives with improved chemotherapeutical properties and extended range of biological activity.

We have demonstrated that reactions of tetraene macrolide antibiotic tetramycin B with aromatic aldehydes and hypophosphoric acid lead to the formation of its hydrophosphoryl derivatives. The studied reaction can be considered as a specific version of the Kabachnik-Fields reaction. In the first stage of the process, the primary amino group of the mycosamine (3-amino-3,6-dideoxy-D-mannose) combines with the carbonyl group of the aromatic aldehyde, with the formation of an azomethine intermediate. In the second stage hypophosphoric acid reacts with the C=N bond of the azomethine intermediate, with the formation of hydrophosphoryl derivatives of tetramycin B.

Biological studies showed that hydrophosphoryl derivatives of tetramycin B were less toxic than initial antibiotic and have expressed antifungal activity against 11 test-cultures of yeast-like fungi of the genus Candida.

Different types of information systems have been applied for efficient synthesis and production of the drugs to be used in diseases diagnostics and treatment. The Intellectual Computer System for optimal choice of the conditions for rational design, synthesis and using in medical practice of novel derivatives of polyene macrolide antibiotics was developed.