An efficient eco-friendly, simple, and green synthesis of some new spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives as potential inhibitors of SARS-CoV-2 proteases: drug-likeness, pharmacophore, molecular docking, and DFT exploration.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has caused a global health crisis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that can cause severe respiratory illness. There is no specific treatment for COVID-19, and the development of new drugs is urgently needed.
Problem Statement: The SARS-CoV-2 main protease (M ^pro ) enzyme is a critical viral enzyme that plays a vital role in viral replication. The inhibition of M ^pro enzyme can be an effective strategy for developing new COVID-19 drugs.
Methodology: An efficient operationally simple and convenient green synthesis method had been done towards a series of novel spiro-N-(4-sulfamoylphenyl)-2-carboxamide derivatives, in ethanol at room temperature in green conditions, up to 90% yield. The molecular structures of the synthesized compounds were verified using spectroscopic methods.The title compounds were subjected to in silico analysis, including Lipinski's rule and ADMET prediction, in addition to pharmacophore modeling and molecular docking against the active site of SARS-CoV-2 target main protease (M ^pro ) enzyme (6LU7). Furthermore, both of the top-ranked compounds (5 and 6) and the standard Nirmatrelvir were subjected to DFT analysis.
Findings: The synthesized compounds exhibited good binding affinity to SARS-CoV-2 Mpro enzyme, with binding energy scores ranging from - 7.33 kcal/mol (compound 6) and - 7.22kcal/mol (compound 5) to - 6.54 kcal/mol (compounds 8 and 9). The top-ranked compounds (5 and 6) had lower HOMO-LUMO energy difference (ΔE) than the standard drug Nirmatrelvir. This highlights the potential and relevance of charge transfer at the molecular level.
Recommendation: These findings suggest that the synthesized spiro-N-(4-sulfamoylphenyl)-2-carboxamide derivatives could be potential candidates for COVID-19 drug development. To confirm these drugs' antiviral efficacy in vivo, more research is required. With very little possibility of failure, this proven method could aid in the search for the SARS-CoV-2 pandemic's desperately needed medications.
(© 2023. The Author(s).)