Modified Thymidine Derivatives as Potential Inhibitors of SARS-CoV: PASS, In Vitro Antimicrobial, Physicochemical and Molecular Docking Studies

Thymidine and thymidine-mimicking derivatives were found to be promising agents against some microorganisms that inhibited the growth of other microorganisms providing effective therapies for several diseases. In the present study, the antimicrobial activities of thymidine and some of its designed derivatives were investigated by employing quantum chemical calculations to assess their thermodynamic and other biochemical parameters. The antimicrobial tests demonstrated that compounds 3, 4, and 14 were the most active against Pseudomonas aeruginosa, Salmonella abony, and Staphylococcus aureus strains, with the calculated minimum inhibitory concentration (MIC) values ranging from 0.32 ± 0.01 to 1.25 ± 0.03 mg ml-1 and minimum bactericidal concentration (MBC) values ranging from 0.32 ± 0.01 to 2.5 ± 0.06 mg ml-1. These derivatives exhibited much stronger biochemical activities than the standard antibacterial drugs. A structure-activity relationship (SAR) study, including in vitro and in silico analysis, revealed that the acyl groups, lauroyl (C12), and myristoyl (C14), in combination with ribose sugar, had the most potent activity against human and fungal pathogens. Prediction of activity spectra for substances (PASS) and quantum calculations, respectively, revealed excellent antimicrobial and thermodynamic properties of the designed thymidine derivatives. A molecular docking study was performed against SARS-CoV main protease protein to investigate its binding energy and binding mode. The designed derivatives exhibited improved binding affinities compared to the parent ligand thymidine. In addition, the ADMET (absorption, distribution, metabolism, elimination, toxicity) studies predicted the pharmacokinetic properties with lower acute oral toxicity, i.e., non-carcinogenic effects of all compounds.