Zirconium catalyzed synthesis of 2-arylidene Indan-1,3-diones and evaluation of their inhibitory activity against NS2B-NS3 WNV protease

• Published in: European journal of medicinal chemistry 2018-04, Vol.149, p.98-109
• Main Authors: Oliveira, Ana Flávia C. da S., de Souza, Ana Paula M., de Oliveira, André S., da Silva, Milene L., de Oliveira, Fabrício M., Santos, Edjon G., da Silva, Ítalo Esposti P., Ferreira, Rafaela S., Villela, Filipe S., Martins, Felipe T., Leal, Daniel H.S., Vaz, Boniek G., Teixeira, Róbson R., de Paula, Sergio O.
• Format: Article
• Language: English
• Subjects: Allosteric Site; Antiviral agents; Catalysis; Hydroxylation; Indan-1,3-dione; Indans - chemical synthesis; Indans - pharmacology; Inhibitory Concentration 50; Knoevenagel condensation; Molecular Docking Simulation; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Viral Nonstructural Proteins - antagonists & inhibitors; West Nile Virus; West Nile virus - enzymology; Zirconium
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.02.037

A simple and efficient Knoevenagel procedure for the synthesis of 2-arylidene indan-1,3-diones is herein reported. These compounds were prepared via ZrOCl2·8H2O catalyzed reactions of indan-1,3-dione with several aromatic aldehydes and using water as the solvent. The 2-arylidene indan-1,3-diones were obtained with 53%-95% yield within 10–45 min. The synthesized compounds were evaluated as inhibitors of the NS2B-NS3 protease of West Nile Virus (WNV). It was found that hydroxylated derivatives impaired enzyme activity with varying degrees of effectiveness. The most active hydroxylated derivatives, namely 2-(4-hydroxybenzylidene)-1H-indene-1,3(2H)-dione (14) and 2-(3,4-dihydroxybenzylidene)-1H-indene-1,3(2H)-dione (17), were characterized as noncompetitive enzymes inhibitors, with IC50 values of 11 μmol L−1 and 3 μmol L−1, respectively. Docking and electrostatic potential surfaces investigations provided insight on the possible binding mode of the most active compounds within an allosteric site. [Display omitted] •A simple and efficient Knoevenagel procedure for the synthesis of 2-arylidene indan-1,3-diones is herein reported.•The synthesized compounds were evaluated as inhibitors of the NS2B-NS3 protease of West Nile Virus (WNV).•The most active hydroxylated derivatives were characterized as noncompetitive enzymes inhibitors, with IC50 values of 11 μmol L−1 and 3 μmol L−1, respectively.•Docking and electrostatic potential surfaces investigations provided insight on the possible binding mode of the most active compounds within an allosteric site.•To the best of our knowledge, this is the first report describing anti-WNV activity of 2-arylidene indan-1,3-dione derivatives.