Synthesis, confirmation based on in vitro and in silico study of thiadiazole-based thiazolidinone scaffolds: An approach toward Covid-19

Coronavirus disease (COVID-19), an infectious disease caused by a newly discovered Coronavirus (severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was targeted in the current research study. Different hybrid thiadiazole based thiazolidinone derivatives were designed and successfully synthesized. Structural validation of novel compounds was achieved via spectroscopy by employing ¹HNMR, ¹³CNMR, HREI-MS. All the synthesized compounds were biologically evaluated to study their potential to inhibit the main protease of SARS-CoV-2. The SAR data revealed that among the synthesized thiadiazole-based thiazolidinone derivatives showed significant inhibitory profile against the targeted enzymes. Different substituted compounds 1 (IC₅₀ = 0.10 µM), 2 (IC₅₀ = 1.43 µM), 4 (IC₅₀ = 2.25 µM), 5 (IC₅₀ = 24.56 µM), 6 (IC₅₀ = 26.47 µM), and 8 (IC₅₀ = 19.59 µM), were found with excellent potentials, even more potent than its standard GC-376 drug (IC₅₀ = 0.439 µM). Among the potent candidates of the series, compound 1 bearing CF₃ at meta and NO₂ at ortho position exhibited the top ranking potential and emerged as the excellent inhibitor of protease of SARS-CoV-2. Furthermore, these potent analogues were subjected to molecular docking study in order to explore their bonding interactions with active sites of SARS-CoV-2 3CL protease. This study was also enriched with ADME analysis to evaluate drug-likeness of lead compounds of the series.