Benzothiazole derivatives as inhibitors of chikungunya virus replicative cycle

AIMS: Chikungunya virus (CHIKV) is the agent of chikungunya fever (CHIKF), a reemerging disease prevalent in tropical regions. With no licensed treatments available, identifying effective antiviral compounds is critical. This study evaluates the antiviral potential of 20 synthetic sulfonamide derivatives against CHIKV. METHODOLOGY: We tested 13 heteroaromatic derivatives containing thiazole, benzimidazole, and benzothiazole (BTA) moieties, along with seven sulfonamides bearing ester and carboxylic acid groups. CHIKV-nanoluc replication was assessed in vitro, and molecular docking and infrared spectroscopy studies were conducted to explore interactions with viral proteins. RESULTS: BTA derivatives 6, 9, 11, and 13 demonstrated potent CHIKV inhibition, with EC50 values between 14.9 and 63.1 µM and selective indexes of 13.8, 5.8, 4.4, and 11, respectively. All compounds acted in the virus post-entry stage, with compound 9 reducing viral replication by 98%. Compound 9 exhibited multi-stage activity, inhibiting CHIKV through virucidal (55%), pre-treatment (69%), and entry (98%) mechanisms. Molecular docking suggested strong binding affinities to CHIKV non-structural proteins and envelope glycoproteins. Infrared spectroscopy corroborated compound 9's interaction with the glycoprotein complex and lipids. CONCLUSIONS: These findings highlight BTA derivatives as promising CHIKV inhibitors. Compound 9's ability to interfere at multiple stages of infection suggests its potential for therapeutic development against CHIKF.