Synthesis and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2‐{6‐[2‐(5‐Phenyl‐4H‐{1,2,4]triazol‐3‐ylsulfanyl)acetylamino]benzothiazol‐2‐ylsulfanyl}acetamide Scaffold

Abstract

In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1 a24, IC50 =3.4±0.2 μM) of the WNV NS2B-NS3 protease. Molecular docking of 1 a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.

Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication

“…During the past few years, allosteric inhibitors of the WNV36 , 37 and DENV-proteases38 have been described. The development of such compounds might be a promising alternative especially for enzymes with poorly defined active sites.…”

Chromosomal integration of hyaluronic acid synthesis (has) genes enhances the molecular weight of hyaluronan produced in Lactococcus lactis

“…Attempts to improve their stability without compromising biological activity proved to be unsatisfactory 10. Other nonpeptidic inhibitors with moderate to good activities are compounds with isothiourea (IC 50 =184 μ M , competitive inhibitor)11 or guanidino ( K i =13±1 μ M )12 moieties, as well as 8‐hydroxyquinoline ( K i =3.2±0.3 μ M , competitive inhibitor),13 isoquinoline (IC 50 =30 μ M ),14 9,10‐dihydro‐3 H ,4a H ‐1,3,9,10a‐tetraaza‐phenanthren‐4‐one ( K i =4.47±0.37 μ M , uncompetitive inhibitor),15a and 2‐{6‐[2‐(5‐phenyl‐4 H ‐[1,2,4]triazol‐3‐ylsulfanyl)acetylamino]benzothiazol‐2‐ylsulfanyl}acetamide ( K i =2.8±0.1 μ M , uncompetitive inhibitor)15b derivatives. To develop more potent WNV inhibitors, there is a need to examine other compounds for their activities and suitability.…”

Benzothiazoles as potential antiviral agents

“…The affinity of the lead was found to improve by several orders of magnitude against WNV NS2B NS3 protease than DENV2 NS2B NS3 protease (Figure 22). [102] Discussion Benzothiazole ring has gained much attention because of its easy functionalisation at various ring positions, which makes them attractive synthetic compounds for designing and development of the novel antiviral drugs in future. Various benzothiazole analogues were reported to have promising antiviral properties.…”