A deep eutectic solvent mediated synthesis of spiro[naphthalene-2,5'-pyrimidine]-4-carbonitriles and their in silico inhibitory potential against the SARS-CoV-2 main protease.

A green and efficient deep eutectic solvent (DES)-mediated multicomponent strategy has been developed for the synthesis of spiro[naphthalene-2,5'-pyrimidine]-4-carbonitriles. This protocol utilizes a biodegradable choline chloride/urea (1 : 2) DES as a sustainable reaction medium, and offers a good yield of targeted products (67-93%), broad substrate scope and high atom economy, while eliminating volatile organic solvents and harsh conditions. The DES can be easily recovered and reused for multiple cycles with minimal loss of efficiency. With operational simplicity, straightforward isolation and excellent recyclability, this approach offers practical and environmental benign multicomponent synthesis of spiro[naphthalene-2,5'-pyrimidine]-4-carbonitriles. The synthesized compounds were also docked and molecular dynamics (MD) simulations was performed to investigate the binding affinity, molecular interactions and stability of our synthesized spiro[naphthalene-2,5'-pyrimidine]-4-carbonitriles with the amino acids of coronavirus main protease (6LU7). All the compounds were found to be potent in comparison with reference inhibitor, remdesivir (-6.62 kcal mol-1) with binding energies ranging from -7.53 to -9.98 kcal mol-1. Overall, the present study demonstrates an efficient and sustainable DES-mediated strategy for the synthesis of biologically important spiro[naphthalene-2,5'-pyrimidine]-4-carbonitrile derivatives with promising antiviral potential against SARS-CoV-2 Mpro. The integration of green synthetic methodology with favourable in silico biological evaluation highlights the medicinal significance of this approach and its potential to promote future antiviral drug discovery research.