N-BENZYL DERIVATIVES OF TETRAENE MACROLIDE ANTIBIOTIC LUCENSOMYCIN: DESIGN, SYNTHESIS, FARMACOLOGICAL STUDIES, ANTIFUNGAL AND ANTIVIRAL ACTIVITY

Lucensomycin, antifungal antibiotic first obtained by Italian investigators, refers to a group of tetraene macrolide antibiotics. Lucensomycin is a product of microbiological synthesis with the help of Streptomyces lucensis producer, its structure, physicochemical, and biomedical properties were studied in detail. However, due to the high toxicity lucensomycin not find application in drug therapy of mycoses in contrast to other tetraene macrolide antibiotics: nystatin and natamycin, which are widely used in a mycological practice for the treatment of many clinical forms of candidosis. It is known that chemical modification of the polyene macrolide antibiotics allows to synthesize of less toxic derivatives with improved chemotherapeutic properties and anextensive spectrum of biological activity.

We have demonstrated that reactions of lucensomycin with p-substituted aromatic aldehydes and sodium cyanoborohydride in the conditions of reductive amination resulted in formation of its N-benzyl derivatives. The pharmacological tests revealed that the acute toxicity (LD₅₀) of obtained derivatives of lucensomycin was 6 times low as that of the starting antibiotic.Biological investigations showed that N-benzyl derivatives of lucensomycin possessed high antifungal activity against a broad range of test cultures, and especially againstsix test cultures of yeast fungi of the genus Candida.It was found that synthesized derivatives of lucensomycinindicatedan expressedantiviral activity in relation to the RNA-containing oncogenic Rous sarcoma virus. Data obtained from studies of N-benzyl derivatives of lucensomycin in relation to the RNA-containing Rous sarcoma virus were of particular interest, as this is a suitable retrovirus model for screening and studying agents with potential use in AIDS.