The crucial functions of acetylcholinesterase (AChE) in neurotransmission and glutathione S‐transferase (GST) in detoxification and cellular protection underscore their pivotal roles as key enzymes, essential for maintaining the integrity of neurological and cellular homeostasis. For this purpose, a series of 1,2,4‐triazine‐sulfonamide hybrids (3a–r) was successfully synthesized, and subsequently evaluated for their inhibitory effects on AChE and GST. The investigation was complemented by molecular docking studies and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions. The synthesized hybrids demonstrated significant promise in inhibiting both AChE and GST activities. Molecular docking analyses provided insights into the interactions between the compounds and the target enzymes, shedding light on potential binding modes and key amino acid residues involved. Furthermore, the study benefited from ADMET predictions, offering valuable information on the compounds' pharmacokinetic properties and potential toxicity. The promising results obtained from this comprehensive approach highlight the potential of these 1,2,4‐triazine‐sulfonamide hybrids as effective inhibitors of AChE and GST, paving the way for further development and optimization in the pursuit of novel therapeutic agents.

Background: Background: The COVID-19 pandemic emerged at the end of 2019 in China and spread rapidly all over the world. Scientists strive to find virus-specific antivirals against COVID-19 disease. This study aimed to assess bioactive some flavolignans as potential SARS-CoV-2 main protease (SARS-CoV-2 Mpro) inhibitors using molecular docking study, molecular dynamic simulations, and ADME analysis. Methods: The detailed interactions between the flavolignans and SARS-CoV-2 Mpro were determined using Autodock 4.2 software. SARS-CoV-2 Mpro was docked with selected flavolignans and the docking results were analyzed by Autodock 4.2 and Biovia Discovery Studio 4.5. The SARS-CoV-2 Mpro-flavolignans’ complexes were subjected to molecular dynamic (MD) simulations for a period of 50 ns. To measure the stability, flexibility, and average distance between the SARS-CoV-2 Mpro and flavolignans, root mean square deviations (RMSD), root mean square fluctuation (RMSF) were calculated, and the binding free energy calculations of SARS-CoV-2 Mpro-flavolignans complexes were found to using the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) method. SwissADME web tools were used to evaluate ADME properties and pharmacokinetic parameters of the flavolignans. Results: The binding energies of the SARS-CoV-2 Mpro- flavolignans’ complexes were identified from the molecular docking of SARS-CoV-2 Mpro. Sinaiticin was found to be the highest binding affinity of -9.4 kcal/mol and formed π-lone pair and pi-alkyl interactions with the catalytic binding residues Glu166 and Cys145. Silychristin, Dehydrosilybin, Hydrocarpin, Silydianin, and 5’-metoxyhydcaprin also showed high binding affinities of -9.3, -9.2, -9.0, -8.7 and -8.6 kcal/mol, respectively. The flavolignans demonstrated strong Carbon H bond interactions with the binding site residues of the Gln192, Gly143, Leu27,Glu166, and Tyr54, and thereby can act as potent inhibitors of the SARS-CoV 2 Mpro. Conclusion: The selected flavolignans obey Lipinski’s rule of five. According to the results obtained from molecular docking studies, molecular dynamic simulations, and ADME analysis. It can be proposed that the flavolignans which can be used to design effective antiviral drug candidates against the SARS-CoV-2, can be tried for promising and effective inhibitors of the SARS-CoV-2 main protease in vitro and in vivo studies.