Novel 1,3-Indanedione-Thiazole Hybrids as Small-Molecule SARS-COV-2 Main Protease Inhibitors With Potential anti-Coronaviral Activity

Abstract

Since arising in 2019, COVID 19 has been causing rapidly-increasing mortality and morbidity rates across the globe. Herein, novel 1,3-indanedione-thiazole hybrids were designed and synthesized as small-molecule SARS-COV-2 Main protease (M^pro) inhibitors with potential anti-covid activity. All target compounds were screened in vitro for their ability to inhibit SARS-COV-2 M^pro. Several compounds displayed potent SARS-COV-2 M^pro inhibition at one-digit IC₅₀ values ranging from 4.3 to 9.9 µM, compared to ritonavir (IC₅₀= 2.4 µM). Moreover, antiviral assay revealed the ability of compounds 12c, 12f, and 16a to significantly inhibit the replication of SARS-COV-2 in Vero cells at EC₅₀ values of 7.79, 2.79 and 1.65 µM, respectively, relative to ritonavir (EC₅₀ = 1.72 µM). Cytotoxicity assay was also conducted. None of the tested compounds exhibited significant cytotoxicity in Vero cells showing CC₅₀ values from 171.77 to 299.96 µM and SI from 38.5 to 178.6 µM. In addition, a docking study revealed proper orientation and well-fitting of title compounds into the binding pocket of SARS-COV-2 Main protease.