Structure-Antifungal Activity Relationships of Polyene Antibiotics of the Amphotericin B Group.

Autores:
Tevyashova AN, Olsufyeva EN, Solovieva SE, Printsevskaya SS, Reznikova MI, Trenin AS, Galatenko OA, Treshalin ID, Pereverzeva ER, Mirchink EP, Isakova EB, Zotchev SB, Preobrazhenskaya MN.

A comprehensive comparative analysis of the structure - antifungal activity relationships for the series of biosynthetically engineered nystatin analogues, their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives was performed. The data obtained revealed the significant influence of the structure of the C7 - C10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in the positions C8 and C9 or C7 and C10. Antibiotics with OH groups at both C7 and C9 positions had the lowest activity. The replacement of the C16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH₃ or COOH group in the position C16, and the structure of the modifying substituent.The most active compounds were tested in vivo to determine maximum tolerated doses (MTD) and antifungal activity on the model of candidosis sepsis in leucopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (3n) and, especially, L-glutamate of 2-(N,N-dimethylamino)ethyl amide of S44HP (2j) with high antifungal activity that are comparable in the in vitro and in vivo tests to AMB, and have better toxicological properties.

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