Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group

Abstract

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.

Fig 1

Structures of the polyene macrolide antibiotics amphotericin B (compound 1) and bioengineered nystatin analogues (compounds 2 to 7).

Fig 2

Antifungal activity (MIC, μg/ml) of the concurrent derivatives of AMB (compounds 1a to 1i) and S44HP (compounds 2a to 2i) compared with the parent antibiotics AMB (compound 1) and S44HP (compound 2) against C. albicans ATCC 14053 (A), C. humicolus ATCC 9949 (B), A. niger ATCC 16404 (C), and F. oxysporum VKM F-140 (D).

Fig 3

Antifungal activity of AMB (compound 1), BSG005 (compound 3), BSG019 (compound 5), and BSG018 (compound 7). The data represented in Fig. 3 and 4 were obtained with a batch of medium RPMI 1640 different from the one used for Fig. 2 and Table 2.

Fig 4

Antifungal activity of AMB (compound 1) and DMAE amides of S44HP (compound 2j), BSG003 (compound 4j), and BSG022 (compound 6j).

Fig 5

Structures of S44HP (compound 2) and BSG005 (compound 3) and of their semisynthetic derivatives.