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Introduction: Thousands of human infective viruses spread worldwide, yet protective measures exist for only a fraction, with internationally accepted vaccines available for an even smaller subset. Treatment options are limited, often restricted to symptom management, as specific antiviral agents remain elusive for most viruses, including the Sindbis virus. Originating in Africa, Sindbis virus, a member of the Alphavirus genus, is primarily transmitted by arthropod vectors, notably mosquitoes, leading to the manifestation of Sindbis fever characterized by symptoms including rash, headache, joint pain, and fatigue, highlighting its significance as a vector-borne human pathogen. While historically associated with major epidemics in northern European countries such as Ockelbo and Pogosta disease, and Karelian fever, the virus's potential for global spread necessitates vigilance and preparedness for the emergence of outbreaks in new regions. In this context, the exploration of repurposed therapeutics, such as derivatives of glycopeptide antibiotics, holds promise for combating Sindbis virus and other viral pathogens, given their observed antiviral activity against a spectrum of viruses including influenza, Dengue virus, West-Nile virus and Human Immundeficiency virus. Methods: We investigated the antiviral efficacy of 26 synthetic antibiotics and derivatives against Sindbis virus in vitro, using Vero E6 cells. Initial compounds included teicoplanin, ristocetin, and vancomycin and their derivatives. Cytotoxicity assessment preceded evaluation of antiviral potential via microscopic analysis, MTT assay, and quantitative PCR analysis to measure changes in viral copy numbers. Results: Four compounds exhibited potent inhibitory effects, with two demonstrating moderate antiviral activity. Among them, a ristocetine derivative (ERJ-552) displayed exceptional potency against Sindbis virus. Further investigations into its mechanism of action were conducted using a time addition assay to determine its antiviral effects during the infection cycle. Discussion: Our findings underscore the potential of repurposed antibiotics and their derivatives in combating Sindbis virus. The identification of ERJ-552 as a potent antiviral compound highlights avenues for further research into novel therapeutics against alphaviruses and other viral pathogens. The study elucidates the importance of exploring existing drugs for new applications in viral therapy. Conclusion: In conclusion, our study demonstrates the antiviral efficacy of synthetic antibiotics and derivatives against Sindbis virus, with ERJ-552 emerging as a particularly promising candidate. These findings contribute to the ongoing efforts to develop effective treatments against emerging viral pathogens, emphasizing the significance of repurposing existing drugs in the fight against infectious diseases.