Synthesis and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 1,3,4,5‐Tetrasubstituted 1H‐Pyrrol‐2(5H)‐one Scaffold

Abstract

West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a large number of human infections each year. There are currently no vaccines or antiviral therapies available for human use against WNV. Therefore, efforts to develop new chemotherapeutics against this virus are highly desired. In this study, a WNV NS2B-NS3 protease inhibitor with a 1,3,4,5-tetrasubstituted 1H-pyrrol-2(5H)-one scaffold was identified by screening a small library of nonpeptidic compounds. Optimization of this initial hit by the synthesis and screening of a focused library of compounds with this scaffold led to the identification of a novel uncompetitive inhibitor ((-)-1a16, IC₅₀ =2.2±0.7 μM) of the WNV NS2B-NS3 protease. Molecular docking of the chiral compound onto the WNV protease indicates that the R enantiomer of 1a16 interferes with the productive interactions between the NS2B cofactor and the NS3 protease domain and is thus the preferred isomer for inhibition of the WNV NS2B-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.…”

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives

“…In the current investigation, another five membered heterocyclic core, 1,3,4-thiadiazole, was incorporated into the final heterocyclic sugar derivatives. Thus, reaction of the acid chloride 3 with ethyl 2-((5-amino-1,3,4thiadiazol-2-yl) thio) acetate (11) 38) led to the formation of the ester functionalized furyl linked 1,3,4-thiadiazolyl derivative 12 in 70% yield. The latter produced ester derivative was converted to the derived acid hydrazide 13 via hydrazinolysis by means of hydrazine hydrate.…”

Antiviral activity of thiadiazoles, oxadiazoles, triazoles and thiazoles

“…Of these, compound 14 showed the best activity. 57 Xu et al 58 prepared a series of 2-(4-methyl-1,2,3-thiadiazolyl)-5-substituted-1,3,4-thiadiazole derivatives. The prepared compounds were tested for their antiviral activity.…”