A series of tricyclic and polycyclic pyrido[1,2-e]purine derivatives were designed and synthesized via a two-step, one-pot reaction of 2,4-dichloro-5-amino-6-methylpyrimidine with pyridine under reflux conditions. Various derivatives of pyrido[1,2-e]purine were also synthesized by substituting the chlorine atom with secondary amines. After careful physiochemical and pharmacokinetic predictions, the inhibitory effects of the synthesized compounds against the main protease of SARS-CoV-2 have been evaluated by molecular docking and molecular dynamics approaches. The in silico results revealed that among all of the studied compounds, the morpholine/piperidine-substituted pyrido[1,2-e]purine derivatives are the best candidates as effective inhibitors of SARS-CoV-2.