Synthesis and Biological Evaluation of Benzothiazolyl-pyridine Hybrids as New Antiviral Agents against H5N1 Bird Flu and SARS-COV-2 Viruses

[Image: see text] A novel series of benzothiazolyl-pyridine hybrids 8a–h and 14a–e were produced from the reaction of enamine derivative 4 with each of the arylcyanoacetamides 5a–h and cyanoacetohydrazides 9a–e. The new products were characterized by spectral techniques (IR, (1)H NMR, (13)C NMR, and MS). Biological evaluation of 8a–h and 14a–e in vitro against H5N1 and SARS-COV-2 viruses showed that several compounds had significant activity. Compounds 8f–h, which contain fluorine atoms, have better activity against H5N1 and anti-SARS-CoV-2 viruses than the other compounds included in this study. Compound 8h has a trifluoromethyl group at position-3 of the phenyl ring and exhibits a high activity against H5N1 virus with 93 and 60% inhibition at concentrations of 0.5 and 0.25 μmol/μL, respectively, among the tested compounds, and it also showed anti-SARS-CoV-2 virus with a half-maximum inhibition rate of 3.669 μM, among the remaining compounds. The mechanism of action of 8f–h, which is expected to be repurposed against COVID-19, was investigated. The results showed that the compounds have virucidal effects at different stages of the three mechanisms of action. Furthermore, compounds 8f–h were found to possess CoV-3CL protease inhibitory activities with IC(50) values of 544.6, 868.2, and 240.6 μg/mL, respectively, compared to IC(50) = 129.8 μg/mL of the standard drug lopinavir. Interestingly, compounds 8f–h also showed high inhibitory activity against the H5N1 virus as well as the SARS-CoV-2 virus. Moreover, compounds 8f–h fit admirably into the active site of the SARS-CoV-2 main protease (PDB ID: 6LU7) using the molecular docking Moe software 2015.10.