A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered
nystatin analogues and 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 C-7 to C-10
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 positions C-8 and C-9 or positions C-7 and C-10.
Antibiotics with
OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 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 C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis
sepsis in leukopenic mice (
cyclophosphamide-induced). Study of our library of semisynthetic polyene
antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (compound 3n) and, especially,
L-glutamate of 2-(N,N-dimethylamino)ethyl
amide of
S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties.