Original article Thiazolidone derivatives as inhibitors of chikungunya virus Surender Singh Jadav a , Barij Nayan Sinha a , Rolf Hilgenfeld b, c , Boris Pastorino d , Xavier de Lamballerie d, ** , Venkatesan Jayaprakash a, * a Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India b Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany c German Center for Infection Research (DZIF), Lübeck, Germany d UMR_D 190 “Emergence des Pathologies Virales”, Aix-Marseille University, IRD French Institute of Research for Development, EHESP French School of Public Health, Marseille, France article info Article history: Received 1 March 2014 Received in revised form 13 October 2014 Accepted 14 October 2014 Available online 16 October 2014 Keywords: Thiazolidinone Antiviral Chikungunya virus nsp2 protease Molecular docking abstract A series of arylalkylidene derivatives of 1,3-thiazolidin-4-one (1e20) were synthesized and tested for their antiviral activity against chikungunya virus (LR2006_OPY1) in Vero cell culture by CPE reduction assay. Five compounds (7e9, 16 and 19) were identified to have anti-ChikV activity at lower micro molar concentration. The compounds 7 , 8, 9, 16 and 19 inhibited the virus at 0.42, 4.2, 3.6, 40.1 and 6.8 mM concentrations respectively. Molecular docking simulation has been carried out using the available X-ray crystal structure of the ChikV nsp2 protease, in order to elucidate the possible mechanism of action. Interaction of ligands with ChikV nsp2 protease (PDB Code: 3TRK) suggested the possible mechanism of protease inhibition to act as potent anti-ChikV agents. © 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction Chikungunya, an emerging arthropod-borne viral infection caused by the chikungunya virus (ChikV, an arbovirus) was first reported from Tanzania during 1952 [1]. A major outbreak has been reported more than 50 years later, during 2005e2007 in Africa and Asia [2,3] that was followed by limited outbreaks in Europe [4] and the US [5].The emergence of a new clinical form of the virus [6] with vector adaptation (Aedes albopictus) [7] explains its geographical spread to developed nations. Threat due to this emerging virus is likely to be high in future if no means to prevent/ treat the infection is developed and made available. To date, there is no effective vaccine or chemotherapeutic agent available. Interferons [8] and their combination with Ribavirin [9] and Mercaptopurine [10] were reported to have antiviral activity against ChikV. Arbidol, an antiviral licensed for the treatment of influenza, was found to inhibit ChikV replication [11]. Extracts of a few plant materials have also been reported to exert anti-ChikV activity [12e18]. The current investigation presents the anti- ChikV activity of benzylidene rhodanine derivatives since rhoda- nine has been identified as a privileged scaffold [19] and reported with antiviral activity against HCV [20,21] and HIV [22]. Molecular docking simulation has been carried out with the recently depos- ited X-ray crystal structure of Chikv nsp2 protease (PDB Code: 3TRK) in order to understand the mechanism of action of the active molecules. 2. Results and discussion 2.1. Chemistry A series of twelve arylalkylidene derivatives of 1,3-thiazolidin- 4-one (1e20) were synthesized following the reaction outlined in Schemes 1 and 2 [23]. Knoevenagel condensation of 2- sulfanylidene-1,3-thiazolidin-4-one (rhodanine) with aromatic/ heteroaromatic aldehydes in the presence of acetic acid and ethanol provided compounds 1e 12 (Scheme 1). Similarly, condensation of 2-amino-4,5-dihydro-1,3-thiazole-4-one (pseu- dothiohydantoin) with aromatic/heteroaromatic aldehydes in the presence of ammonium acetate and glacial acetic acid provided compounds 13e20 (Scheme 2). The resultant precipitates were recrystallized with ethanol to obtain pure final product. All the final compounds were found to have melting points closely matching * Corresponding author. ** Corresponding author. E-mail addresses: Xavier.De-Lamballerie@medecine.univ-mrs.fr (X. de Lamballerie), drvenkatesanj@gmail.com (V. Jayaprakash). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.10.042 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 89 (2015) 172e178