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  • Discovery and Hit-to-Lead Optimization of Benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa [Elektronski vir]
    Cotman, Andrej Emanuel ...
    We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting ... from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
    Source: Journal of medicinal chemistry [Elektronski vir]. - ISSN 1520-4804 (Vol. 66, no. 2, 2023, str. 1380-1425)
    Type of material - e-article ; adult, serious
    Publish date - 2023
    Language - english
    COBISS.SI-ID - 138544899

    Link(s):

    https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c01597
    Repository of the University of Ljubljana – RUL
    DOI

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