title: 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.
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 μM). The IC(50) values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, 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.
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Huiguo
authors.initials: H
authors.lastname: Lai
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Dou
authors.forename: Sridhar
authors.initials: S
authors.lastname: Aravapalli
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Teramoto
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
authors.forename: Tom M
authors.initials: TM
authors.lastname: Mwania
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Alliston
authors.forename: David M
authors.initials: DM
authors.lastname: Eichhorn
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Padmanabhan
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D014901:West Nile Fever / Q000188:drug therapy; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000998:Antiviral Agents; D010069:Oxadiazoles; D011480:Protease Inhibitors; D014230:Triazoles; C573968:benzisothiazol-3(2H)-one; D010447:Peptide Hydrolases