Synthesis and in Silico Investigation of Organoselenium-Clubbed Schiff Bases as Potential M pro Inhibitors for the SARS-CoV-2 Replication.

Simple Summary: The coronavirus was declared a worldwide pandemic for the first time in December 2019. Although vaccination reduces the risk of severe illness and death, no vaccine is 100% foolproof. Recently, the COVID-19 primary protease has become a promising therapeutic target. During the preceding three years, many low molecular weight chemical libraries were tested for their potent antiviral potency against SARS-CoV-2. Many studies focused on organoselenium compounds due to their potential antiviral activities. Herein, new organoselenium-based Schiff bases were successfully synthesized and evaluated for their potential to inhibit the SARS-CoV-2 Mpro main protease, which is essential for virus replication. Since the first report of the organoselenium compound, ebselen, as a potent inhibitor of the SARS-CoV-2 Mpro main protease by Z. Jin et al. (Nature, 2020), different OSe analogs have been developed and evaluated for their anti-COVID-19 activities. Herein, organoselenium-clubbed Schiff bases were synthesized in good yields (up to 87%) and characterized using different spectroscopic techniques. Their geometries were studied by DFT using the B3LYP/6–311 (d, p) approach. Ten FDA-approved drugs targeting COVID-19 were used as model pharmacophores to interpret the binding requirements of COVID-19 inhibitors. The antiviral efficiency of the novel organoselenium compounds was assessed by molecular docking against the 6LU7 protein to investigate their possible interactions. Our results showed that the COVID-19 primary protease bound to organoselenium ligands with high binding energy scores ranging from −8.19 to −7.33 Kcal/mol for 4c and 4a to −6.10 to −6.20 Kcal/mol for 6b and 6a. Furthermore, the docking data showed that 4c and 4a are good Mpro inhibitors. Moreover, the drug-likeness studies, including Lipinski's rule and ADMET properties, were also assessed. Interestingly, the organoselenium candidates manifested solid pharmacokinetic qualities in the ADMET studies. Overall, the results demonstrated that the organoselenium-based Schiff bases might serve as possible drugs for the COVID-19 epidemic. [ABSTRACT FROM AUTHOR]