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    Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents

    Abo-Ashoura, M.F. and Eldehnab, W.M. and George, R.F. and Abdel-Azizd, M.M. and Elaasser, M.M. and Abdel Gawad, N.M. and Gupta, Antima and Bhakta, Sanjib and Abou-Seric, S.M. (2018) Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents. European Journal of Medicinal Chemistry 160 , pp. 49-60. ISSN 0223-5234.

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    Abstract

    In connection with our research program on the development of novel anti-tubercular candidates, herein we report the design and synthesis of two different sets of indole-thiazolidinone conjugates (8a,b; 11a-d) and (14a-k; 15a-h). The target compounds were evaluated for their in vitro antibacterial and antifungal activities against selected human pathogens viz. Staphylococcus aureus (Gram positiveve), Pseudomonas aeruginosa, Escherichia coli (Gram negative), Mycobacterium tuberculosis (Acid-fast bacteria), Aspergillus fumigates and Candida albicans (fungi). Moreover, eukaryotic cell-toxicity was tested via an integrated ex vivo drug screening model in order to evaluate the selective therapeutic index (SI) towards antimicrobial activity when microbes are growing inside primary immune cells. Also, the cytotoxicity towards a panel of cancer cell lines and human lung fibroblast normal cell line, WI-38 cells, was explored to assure their safety. Compound 15b emerged as a hit in this study with potent broad spectrum antibacterial (MIC: 0.39-0.98 µg/ml) and antifungal (MIC: 0.49-0.98 µg/ml) activities, in addition to its ability to kill mycobacteria M. aurum inside an infected macrophage model with good therapeutic window. Moreover, compound 15b displayed promising activity towards resistant bacteria strains MRSA and VRE with MIC values equal 3.90 and 7.81 µg/mL, respectively. These results suggest compound 15b as a new therapeutic lead with good selectivity for further optimization and development.

    Metadata

    Item Type: Article
    School: School of Science > Biological Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Sanjib Bhakta
    Date Deposited: 08 Oct 2018 10:05
    Last Modified: 13 Jan 2021 19:28
    URI: https://eprints.bbk.ac.uk/id/eprint/24439

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