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Molecular docking, expounding the chemo-, regio-selectivity, and the mechanism of [3 + 2] cycloloaddition reaction between nitrile-imine and (thio)-chalcone

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Abstract

The study explores the application of molecular electron density theory, focusing on the [2 + 3] cycloaddition mechanisms between nitrile-imine and chalcone or thiochalcone. Density Functional Theory (DFT) calculations employing the B3LYP/6–311(d,p) methodology are utilized to determine activation and reaction energies, as well as reactivity indices. Through investigation of conceptual DFT indices, nitrile-imine is identified as a nucleophile, while chalcone and thiochalcone act as electrophiles in the reaction. The reactions exhibit both chemo- and regiospecifics, as confirmed by Parr functions, Electron Localization Function (ELF) survey, and energetic analysis, consistent with experimental results. ELF analysis suggests a two-phase mechanism for these [2 + 3] cycloadditions. Furthermore, docking studies on the resultant products reveal enhanced interaction energies with proteins due to the presence of oxygen and sulfur atoms, in their interaction with the crystal structure of COVID-19 main protease (PDB ID: 6LU7) and paves a ways for manufacturing innovation.

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Acknowledgements

The authors extend their appreciation to the Researchers Supporting Project number (RSP2024R15), King Saud University, Riyadh, Saudi Arabia.

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Correspondence to Mohammed El idrissi or Abdellah Zeroual.

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Ryachi, K., idrissi, M.E., Mohammad-Salim, H. et al. Molecular docking, expounding the chemo-, regio-selectivity, and the mechanism of [3 + 2] cycloloaddition reaction between nitrile-imine and (thio)-chalcone. Monatsh Chem 155, 697–707 (2024). https://doi.org/10.1007/s00706-024-03221-4

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