Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold

Abstract

Dengue and West Nile viruses (WNV) are mosquito-borne members of flaviviruses that cause significant morbidity and mortality. There is no approved vaccine or antiviral drugs for human use to date. In this study, a series of functionalized meta and para aminobenzamide derivatives were synthesized and subsequently screened in vitro against Dengue virus and West Nile virus proteases. Four active compounds were identified which showed comparable activity toward the two proteases and shared in common a meta or para(phenoxy)phenyl group. The inhibition constants (Ki) for the most potent compound 7n against Dengue and West Nile virus proteases were 8.77 and 5.55 μM, respectively. The kinetics data support a competitive mode of inhibition of both proteases by compound 7n. This conclusion is further supported by molecular modeling. This study reveals a new chemical scaffold which is amenable to further optimization to yield potent inhibitors of the viral proteases via the combined utilization of iterative medicinal chemistry/structure-activity relationship studies and in vitro screening.

Combined treatment of adenosine nucleoside inhibitor NITD008 and histone deacetylase inhibitor vorinostat represents an immunotherapy strategy to ameliorate West Nile virus infection

“…Multiple efforts so far have led to the discovery of several small molecule-based inhibitors targeting viral proteins critical for WNV replication (Aravapalli et al, 2012; Lim and Shi, 2013; Mueller et al, 2008; Stahla-Beek et al, 2012). However, data on their efficacy in vivo is limited and not promising.…”

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

“…However, the binding affinity values obtained with these molecules were not as good as those calculated for the molecules suggested in this paper. The PDB crystal structure 2FOM was also used for docking with some molecules that were reported as not being active inhibitors for dengue protease [46][47][48]. The molecular structure of inhibitors reported for other proteases (HCV, WNV, Dengue and HIV), as well as those known as not active inhibitors for dengue protease, that were docked onto the crystal structure of the dengue NS2B/NS3 complex (PDB: 2FOM), are shown in Table S3.…”

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).…”