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    Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: Potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases

    Date
    2013-01
    Author
    Lai, Huiguo
    Dou, Dengfeng
    Aravapalli, Sridhar
    Teramoto, Tadahisa
    Lushington, Gerald H.
    Mwania, Tom M.
    Alliston, Kevin R.
    Eichhorn, David M.
    Padmanabhan, Radhakrishnan
    Groutas, William C.
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    Citation
    Lai, Huiguo; Dou, Dengfeng; Aravapalli, Sridhar; Teramoto, Tadahisa; Lushington, Gerald H.; Mwania, Tom M.; Alliston, Kevin R.; Eichhorn, David M.; Padmanabhan, Radhakrishnan; Groutas, William C. 2013. Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: Potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases. Bioorganic & Medicinal Chemistry, v.21 no.1 pp.102-113
    Abstract
    1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted considerable interest in drug discovery, including as antibacterial and antifungal agents. In this study, a series of functionalized 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole hybrid derivatives were synthesized and subsequently screened against Dengue and West Nile virus proteases. Ten out of twenty-four compounds showed greater than 50% inhibition against DENV2 and WNV proteases ([I] = 10 mu M). The IC50 values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 +/- 0.06 and 4.22 +/- 0.07 mu M, respectively. The kinetics data support a competitive mode of inhibition by compound 7n. Molecular modeling studies were performed to delineate the putative binding mode of this series of compounds. This study reveals that the hybrid series arising from the linking of the two scaffolds provides a suitable platform for conducting a hit-to-lead optimization campaign via iterative structure-activity relationship studies, in vitro screening and X-ray crystallography.
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    URI
    http://dx.doi.org/10.1016/j.bmc.2012.10.058
    http://hdl.handle.net/10057/5605
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