s44hp has been researched along with Sepsis* in 2 studies
2 other study(ies) available for s44hp and Sepsis
Article | Year |
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Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group.
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. Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Cyclophosphamide; Drug Evaluation, Preclinical; Leukopenia; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Nystatin; Polyenes; Sepsis; Small Molecule Libraries; Structure-Activity Relationship | 2013 |
Synthesis and study of the antifungal activity of new mono- and disubstituted derivatives of a genetically engineered polyene antibiotic 28,29-didehydronystatin A1 (S44HP).
Mono- and disubstituted novel derivatives of the heptaene nystatin analog 28,29-didehydronystatin A(1) (S44HP, 1) were obtained by chemical modification of the exocyclic C-16 carboxyl and/or an amino group of mycosamine moiety. The strategy of preparation of mono- and double-modified polyene macrolides was based on the use of intermediate hydrophobic N-Fmoc (9-fluorenylmethoxycarbonyl) derivatives that facilitated the procedures of isolation and purification of new compounds. The antifungal activity of the new derivatives was first tested in vitro against yeasts and filamentous fungi, allowing the selection of the most active compounds that were subsequently tested for acute toxicity in mice. 2-(N,N-dimethylamino)ethylamide of 1 (2) and 2-(N,N-dimethylamino)ethylamide of N-fructopyranosyl-28,29-didehydronystatin A(1) (2a) were then selected for further evaluation in a mouse model of disseminated candidosis, and showed high efficacy while being considerably less toxic than amphotericin B (AmB). The compound with improved water solubility (2G, L-glutamic acid salt of 2) showed better chemotherapeutic activity than AmB in the mouse model of candidosis sepsis on a leucopenic background. Very low antifungal effect was seen after treatment with AmB, even if it was used in maximum tolerated dose (2 mg kg(-1)). Unlike AmB, compound 2G exhibited high activity in doses from 0.4 up to 4.0 mg kg(-1), despite leucopenic conditions. Topics: Animals; Antifungal Agents; Candidiasis; Genetic Engineering; Lethal Dose 50; Male; Mice; Molecular Structure; Nystatin; Sepsis; Structure-Activity Relationship | 2010 |