Structurally diverse piperazine-based compounds hybrid with thiadiazole, isatin or with sulfur/nitrogen, functionalities were synthesized. The structures of the new compounds were established based on their spectral data and elemental analysis. The physicochemical, bioactivity scores and pharmacokinetic behavior of all the prepared ligands were evaluated using in silico computational tools. The new piperazine ligands have been screened for their inhibition activity against SARS-CoV-2 protease enzyme using molecular docking analysis. The docking studies showed that all the ligands have been docked with negative dock energy onto the target protease protein. Moreover, Molecular interaction studies revealed that SARS-CoV-2 protease enzyme had strong hydrogen bonding interactions with piperazine ligands. The present in silico study thus, provided some guidance to facilitate drug design targeting the SARS-CoV-2 main protease.