•A novel series of adenosine analogues were synthesized as antiviral agents.•The phenyl substitution of piperazine moiety may more effective.•Compounds 8b exhibited better inhibitory activities against CVB3 than Ribavirin.•The target compounds were designed by computer simulation.•These kinds of adenosine analogues might be developed as potent antiviral agents.A series of adenosine analogues were synthesized and their biological evaluation was tested against Coxsackie virus B3 (CVB3) and Herpes simplex virus type 1(HSV-1) in HEp-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were calculated. Analogues with piperazine derivatives 8b showed promising activities against CVB3 with a lower IC50value and higher selectivity index, their efficacy was better than that of the commercialized medicine, Ribavirin. These described adenosine analogues exhibit potent antiviral activities against several viruses, and offer new leads for further development.