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    Optimization of a benzothiazole indolene scaffold targeting bacterial cell wall assembly

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    Author
    Chauhan, J.
    Fletcher, S.
    de Leeuw, E.P.H.
    Yu, W.
    MacKerell, A.D., Jr.
    Fletcher, S.
    Date
    2020
    Journal
    Drug Design, Development and Therapy
    Publisher
    Dove Medical Press Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.2147/DDDT.S226313
    Abstract
    Background: The bacterial cell envelope is comprised of the cell membrane and the cell wall. The bacterial cell wall provides rigidity to the cell and protects the organism from potential harmful substances also. Cell wall biosynthesis is an important physiological process for bacterial survival and thus has been a primary target for the development of antibacterials. Antimicrobial peptides that target bacterial cell wall assembly are abundant and many bind to the essential cell wall precursor molecule Lipid II. Methods: We describe the structure-to-activity (SAR) relationship of an antimicrobial peptide-derived small molecule 7771-0701 that acts as a novel agent against cell wall biosynthesis. Derivatives of compound 7771-0701 (2-[(1E)-3-[(2E)-5,6-dimethyl-3-(prop2-en-1-yl)-1,3-benzothiazol-2-ylidene]prop-1-en-1-yl]-1,3,3-trimethylindol-1-ium) were generated by medicinal chemistry guided by Computer-Aided Drug Design and NMR. Derivatives were tested for antibacterial activity and Lipid II binding. Results: Our results show that the N-alkyl moiety is subject to change without affecting functionality and further show the functional importance of the sulfur in the scaffold. The greatest potency against Gram-positive bacteria and Lipid II affinity was achieved by incorporation of a bromide at the R3 position of the benzothiazole ring. Conclusion: We identify optimized small molecule benzothiazole indolene scaffolds that bind to Lipid II for further development as antibacterial therapeutics. Copyright 2020 Chauhan et al.
    Sponsors
    This work was supported by Center for Biomolecular Therapeutics (PR155EDL1; UMB), the UMB Computer-Aided Drug Design Center, a UM Ventures Seed grant and Center for Maryland Advanced Ventures grant to EdL.
    Keyword
    Antibiotics
    Cell wall
    Drug development
    Lipid II
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85079438995&doi=10.2147%2fDDDT.S226313&partnerID=40&md5=a38cc37bf6146c91c76f2273571e8909; http://hdl.handle.net/10713/12074
    ae974a485f413a2113503eed53cd6c53
    10.2147/DDDT.S226313
    Scopus Count
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    UMB Open Access Articles 2020

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