The emergence and re-emergence of new- and old-diseases represent the significant challenge for humankind, where this is not prepared for it.^1–3 Among these, zoonotic diseases account for billions of cases of human illness and thousands of deaths around the world, constituting a global public health problem.^4,5 Alphavirus genus belongs to the Togaviridae family and includes more than 30 species of enveloped viruses.^6–8 Chikungunya virus (CHIKV) is composed of (+)ssRNA, structural, and non-structural proteins.^9–11 Frequently, infectious diseases caused by CHIKV are characterized by inflammation and pain of the musculoskeletal tissues, which often these are accompanied by swelling in the joints, resulting in cartilage damage.^12,13 Currently, there are no licensed vaccines or chemotherapeutic agents able to prevent or treat CHIKV infections.^14–16 Furthermore, the major part of the available antiviral agents and researches is focused on small synthetic molecules against Herpes, HIV, and Influenza viruses.¹⁷ However, several acrylamide compounds have been synthesized in different anti-CHIKV studies, where they have demonstrated promising antiviral activity, suggesting which this chemical class could be used as a scaffold for designing of new antiviral agents.^18–20 Considering these facts, this research aims to explore the potential in vitro anti-CHIKV activity of several substituted acrylamide derivatives. In sense, a meticulous virtual screening was performed by using molecular dynamics simulations and docking for 132 acrylamide analogs toward the six more essential biological targets from CHIKV, such as nsP2 (PDB: 3TRK), nsP2/helicase (PDB: 6JIM), nsP3 (PDB: 3GPO), immature E protein (PDB: 3N40), E protein (PDB: 3N41), and capsid (PDB: 5H23). Subsequently, the ten most promising acrylamides were selected and synthesized by amide-coupling reactions, employing TBTU and DIPEA as coupling-agent and base, respectively. All derivatives were characterized by ¹H and ¹³C NMR, HLPC, purity (≥ 96%), and melting point. Then, the cytotoxicity MTT assay was performed for ten acrylamides (GP01-10) toward Vero E6 line cells at 20 and 40 µM concentrations. For the antiviral activity assays, CHIKV adsorption was performed for 2h in Vero E6 cells followed by the treatment with promising compounds at 40 µM for 72h and cell viability analysis (MTT assay). As result, it was observed that acrylamides GP03 and 09 exhibited weak viral inhibition values (49 and 32% at 40 µM, respectively). In contrast, the acrylamide GP07 displayed a significant in vitro anti-CHIKV activity, with an inhibition value of 81%. Based on this result, various molecular docking simulations was performed to suggest a potential CHIKV-target for GP07. From these, it was observed that the GP07 has a high affinity towards E protein, where it was able to interact with Cys⁴⁷⁰, Lys⁴⁷¹, Asp⁴⁷², Tyr⁴⁷⁸, Ser⁴⁷⁹, Cys⁴⁸⁰, Lys⁴⁸¹, Leu⁶²³, and Val⁶²² amino acid residues by van der Waals interactions. To confirm the antiviral activity, the intracellular labeling of virus was performed by using a monoclonal anti-CHIKV antibody (A54Q)/mouse anti-IgG Alexa Fluor 488, and the percentage of CHIKV-positive cells was detected by flow cytometry. As result, GP07 was able to reduce the percentage of CHIKV-positive cells from 74.8 to 0.91%, 48h post-treatment. In conclusion, all virtual simulations were corroborated by experimental results and the compound GP07 was identified as a promising anti-CHIKV agent for designing new drugs in the future.