XRD/DFT, Hirshfeld surface analysis and molecular modelling simulations for unfolding reactivity of newly synthesized vanillin derivatives: excellent optical, NLO and protein binding efficiency

Abstract

New vanillin derivatives, namely, ethyl (4-formyl-2-methoxyphenoxy)acetate (2a) and 2-(4-formyl-2-methoxyphenoxy)-N-phenylacetamide (2b), respectively, were synthesized and characterized by NMR (¹H and ¹³C), IR, mass spectra and confirmed by single-crystal X-ray analysis. Hirshfeld surface (HS) analysis was performed to probe intra- and intermolecular interactions and surface reactivity. 2D fingerprint plots (FP) were used to study the nature and percentage contribution of intermolecular interactions leading to the formation of the crystal unit. Density functional theory (DFT) simulations were used to obtain the electronic structure and reactivity of the new molecules. Natural population analysis (NPA) and frontier molecular orbital (FMO) calculations reveal significant charge transfer and a reduced HOMO-LUMO gap up to 4.34 eV for 2b. Bader’s quantum theory of atoms in molecules (QTAIM) study is utilized to understand the surface topological and bonding nature of 2a and 2b. The performed molecular electrostatic potential (MESP) and density of states (DOS) study further suggest sites likely to be attractive to incoming reagents. At the same time, hyperpolarizability (β_o) is used to characterize the nonlinear optical properties, and TD-DFT study shows the excitation energy and absorption behavior. In silico studies were performed, including docking, binding free energies (MMBGSA) and molecular dynamics simulations. Compounds 2a and 2b were docked with RdRp of SARS-Cov-2, and the MMBGSA for 2a and 2b were −30.70 and −28.47 kcal/mol, respectively, while MD simulation showed the stability of protein-ligand complexes.

Communicated by Ramaswamy H. Sarma

Keywords:

• vanillin
• X-ray analysis
• TD-DFT, NBO-NLO studies
• DOS
• molecular docking and dynamics

Acknowledgments

The authors extend their appreciation to the Researchers Supporting Project, King Saud University, Riyadh, Saudi Arabia for funding this work through grant No RSP2024R353.

Disclosure statement

No potential conflict of interest was reported by the author(s)

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was funded by Researchers Supporting Project No RSP2024R353, King Saud University, Riyadh, Saudi Arabia.