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 IC50 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.

Synthesis and Biological Activities of 1, 3, 4-Oxadiazole Derivatives: A Review of Literature.

“…In this some of them were most potent and selective against HDAC. 1118 Scheme 10:-Lai H, et al, [9] (2012) were synthesised a series of functionalized 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole hybrid derivatives (scheme: 11) and screened against Dengue and West Nile virus proteases. …”

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

“…This crystallographic structure has been used recently by several authors for in silico molecular docking approaches [22][23][24]. The 3D structure of the protein was prepared using the SYBYL 8.1 software package (Tripos, Inc., 2008) by removing all of the water molecules and substructures that were present.…”

The flavivirus protease as a target for drug discovery

“…To explore more small molecular inhibitors for the protease, both in silico -based and protein-based HTS has been developed (Aravapalli S, et al, 2012; Deng J, et al, 2012; Ekonomiuk D, et al, 2009; Ekonomiuk D, et al, 2009; Ezgimen M, et al, 2012; Gao Y, et al, 2013; Johnston P A, et al, 2007; Knehans T, et al, 2011; Lai H, et al, 2013; Lai H, et al, 2013; Mueller N H, et al, 2008; Nitsche C, et al, 2011; Samanta S, et al, 2012; Steuer C, et al, 2011; Tiew K C, et al, 2012; Tomlinson S M, et al, 2012; Tomlinson S M, et al, 2009). Several small molecule inhibitors were identified possessing low micromolar or high nanomolar inhibition activities for the WNV and DENV proteases (Bodenreider C, et al, 2009; Cregar-Hernandez L, et al, 2011; Ekonomiuk D, et al, 2009; Johnston P A, et al, 2007; Knehans T, et al, 2011; Lai H, et al, 2013; Mueller N H, et al, 2008; Sidique S, et al, 2009; Tomlinson S M, et al, 2011; Tomlinson S M, et al, 2009; Yang C C, et al, 2011).…”