COVID-19 is a rapidly spreading infectious disease caused by a novel beta coronavirus SARS-CoV-2. During the 1980's coronavirus, genomic RNA was transcribed into a set of subgenomic mRNAs that encode viral proteins containing a leader sequence derived from the 5' end of the genome. The subgenomic mRNAs are transcribed from negative-strand RNAs, synthesized for the full-length genomic RNA - a unique mechanism, presumed to occur by a process involving viral polymerase jumping from one part of the genome template to another, leading to high rate of recombination for coronaviruses, playing role in viral interspecies infections. The sequence of SARS-CoV-2 confined that spike protein has furin cleavage site in the S1/S2 junction different from SARS-CoV and other closely related viruses. This has proved the possibility of Protease inhibitors as antivirals has led to the speculation about virulence and pathogenesis, and it is also possible that this new furin site may serve as a marker to identify a possible precursor virus. This novel human coronavirus (SARS-CoV-2) has resulted in a large number of fatalities and incapacitated human health system. No treatment is available, and a vaccine will not be available for several months. Hence, the protease of coronavirus is a promising target for antiviral drug discovery.We herein report a new generation of thiazolidinone derivatives, inhibitors of SARS-CoV-2 coronavirus protease that incorporated thiazolidinone heterocycles as N-terminal capping groups of the peptide moiety. The compounds were extensively characterized with respect to inhibition of various proteases, inhibition mechanism, membrane permeability, antiviral activity. Our research group has recently designed a one-pot three-component reaction and its mechanism was studied through DFT. Further, a library of the molecules based on the products is designed. These novel molecules were screened through ADMET and molecular docking to find out the potential inhibitor of SARS-CoV-2 protease, as they may have competitive inhibition mechanisms, in correlation with their membrane permeability, a more pronounced antiviral activity.