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

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Authors
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.
Issue Date
2013-01
Type
Article
Language
en_US
Keywords
1,2-Benzisothiazol-3(2H)-ones , 1,3,4-Oxadiazoles , Dengue virus protease , West Nile virus protease
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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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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
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PERGAMON-ELSEVIER SCIENCE LTD
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ISSN
0968-0896
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