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Schiff bases encompassing a 1,2,3-triazole motif were synthesized using an efficient multi-step synthesis. The formations of targeted Schiff base ligands were confirmed by different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, and CHN analysis). The spectral data analysis revealed that the newly designed hydrazones exist as a mixture of trans-E and cis-E diastereomers. Densityfunctional theory calculations (DFT) for the Schiff bases showed that the trans-trans form has the lowest energy structure with maximum stability compared to the other possible geometrical isomers that could be present due to the orientation of the amidic NH–C=O group. The energy differences between the trans-trans on one side and syn-syn and syn-trans isomers on the other side were 9.26 and 5.56 kcal/mol, respectively. A quantitative structure-activity relationship investigation was also performed in terms of density functional theory. The binding affinities of the newly synthesized bases are, maybe, attributed to the presence of hydrogen bonds together with many hydrophobic interactions between the ligands and the active amino acid residue of the receptor. The superposition of the inhibitor N3 and an example ligand into the binding pocket of 7BQY is also presented. Further interesting comparative docking analyses were performed. Quantitative structure-activity relationship calculations are presented, illustrating possible inhibitory activity. Further computer-aided cytotoxicity analysis by Drug2Way and PASS online software was carried out for Schiff base ligands against various cancer cell lines. Overall, the results of this study suggest that these Schiff base derivatives may be considered for further investigation as possible therapeutic agents for COVID-19.

The highly contagious nature of Covid‐19 attracted us to this challenging area of research, mainly because the disease is spreading very fast and until now, no effective method of a safe treatment or a vaccine is developed. A library of novel 1,2,3‐triazoles based 1,2,4‐triazole, 1,3,4‐oxadiazole and/or 1,3,4‐thiadiazole scaffolds were designed and successfully synthesized. Different spectroscopic tools efficiently characterized all the newly synthesized hybrid molecules. An interesting finding is that some of the newly designed compounds revealed two isomeric forms. The ratio is affected by the size of the attached group as well as the type of the heteroatom forming the side ring attached to the central 1,2,3‐triazole ring. The experimental spectroscopic data is in agreement with the DFT calculations at B3LYP 6‐31G (d,p) with regard to the geometrical conformation of the prepared compounds. The DFT results revealed that the stability of one isomeric form over the other in the range of 0.057–0.161 Kcal mol−1. A docking study was performed using PyRx and AutoDockVina to investigate the activity of the prepared 1,2,3‐triazoles as antiviral agents. Bond affinity scores of the 1,2,3‐triazole derivatives were detected in the range of −6.0 to −8.8 kcal/mol showing binding to the active sites of the 6LU7 protease and hence could be anticipated to inhibit the activity of the enzyme. Verification of the docking results was performed using the Mpro alignment of coronaviruses substrate‐binding pockets of COVID‐19 against the ligands. As per these results, it can be proposed that the title hybrid molecules are acceptable candidates against COVID‐19 for possible medicinal agents., A series of novel 1,2,3‐triazole molecular hybrids with 1,2,4‐triazole, 1,3,4‐thiadiazole and/or 1,3,4‐oxadiazole tethers have been successfully synthesized as potential inhibitors against Covid‐19 Main Protease.