New spirooxindole-benzothiazole hybrids incorporating a trifluoromethyl moiety as antiviral agents: Design, synthesis, crystal structure analysis, and in silico studies

Abstract

Developing antiviral agents for RNA viruses is crucial due to their global health impact, high mutation rates, and pandemic potential. Most RNA virus infections still lack vaccines or specific antiviral treatments. New spirooxindole-benzothiazole hybrids (4a-e and 5a-m) incorporating a trifluoromethyl moiety were synthesized from treating 1H-indole-2,3-diones with 2-amino-4-(trifluoromethyl)benzenethiol in ethanol. Structures of compounds 4a-e and 5a-m were confirmed by analytical and spectral data and single crystal X-ray analysis. The antiviral effects of the compounds were tested against Chikungunya virus (CHIKV), Parainfluenza virus 3 (PIV3), Zika virus (ZIKV), and Enterovirus 71 (EV-A71). Compounds 4a-c, 5c-h, and 5j-m against CHIKV, and compounds 4a, 5d, 5g, and 5l against PIV3 were selected for further evaluation. R<inf>1</inf>= methyl and R<inf>2</inf>= 5,7-dichlorine substituted compound 5m was found to have significant antiviral activity against CHIKV (EC<inf>50</inf>= 0.86 µM, SI= 10–20). The three-dimensional structures of compounds 5l and 5m were determined by single crystal X-ray analysis, and combined molecular docking and molecular dynamics simulation studies were performed to predict their interactions with PIV3 and CHIKV. © 2025 Elsevier B.V., All rights reserved.