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ID: ALA4387762
Journal: Bioorg Med Chem
Title: Multicomponent synthesis of α-acylamino and α-acyloxy amide derivatives of desmycosin and their activity against gram-negative bacteria.
Authors: Budragchaa T, Westermann B, Wessjohann LA.
Abstract: Bacterial resistance to the existing drugs requires constant development of new antibiotics. Developing compounds active against gram-negative bacteria thereby is one of the more challenging tasks. Among the many approaches to develop successful antibacterials, medicinal chemistry driven evolution of existing successful antibiotics is considered to be the most effective one. Towards this end, the C-20 aldehyde moiety of desmycosin was modified into α-acylamino and α-acyloxy amide functionalities using isonitrile-based Ugi and Passerini reactions, aiming for enhanced antibacterial and physicochemical properties. The desired compounds were obtained in 45-93% yield under mild conditions. The antibacterial activity of the resulting conjugates was tested against gram-negative Aliivibrio fischeri. The antibiotic strength is mostly governed by the amine component introduced. Thus, methylamine derived desmycosin bis-amide 4 displayed an enhanced inhibition rate vs. desmycosin (99% vs. 83% at 1 µM). Derivatives with long acyclic or bulky amine and isocyanide Ugi components reduced potency, whereas carboxylic acid reagents with longer chain length afforded increased bioactivity. In Passerini 3-component products, the butyric ester amide 22 displayed a higher activity (90% at 1 µM) than the parent compound desmycosin (2).
CiteXplore: 31229422