Insights into the crystal structure investigation and virtual screening approach of quinoxaline derivatives as potent against c-Jun N-terminal kinases 1

Abstract

Quinoxaline derivatives are an important class of heterocyclic compounds in which N replaces one or more carbon atoms of the naphthalene ring and exhibit a wide spectrum of biological activities and therapeutic applications. As a result, we were encouraged to explore a new synthetic approach to quinoxaline derivatives. In this work, we synthesized two new derivatives namely, ethyl 4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (2) and 3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (3) respectively. Their structures were confirmed by single-crystal X-ray analysis. Hirshfeld surface (HS) analysis is performed to understand the nature and magnitude of intermolecular interactions in the crystal packing. Density functional theory using the wb97xd/def2-TZVP method was chosen to explore their reactivity, electronic stability and optical properties. Charge transfer (CT) and orbital energies were analyzed via natural population analysis (NPA), and frontier molecular orbital (FMO) theory. The calculated excellent static hyperpolarizability (β_o) indicates nonlinear optical (NLO) properties for 2 and 3. Both compounds show potent activity against c-Jun N-terminal kinases 1 (JNK 1) based on structural activity relationship studies, further subjected to molecular docking, molecular dynamics and ADMET analysis to understand their potential as drug candidates.

Communicated by Ramaswamy H. Sarma

Keywords:

• quinoxaline
• crystal structure
• DFT study
• ADMET
• molecular docking and dynamics simulations

Data availability statement

CCDC Nos. 2314473 for 2, and 2314474 for 3. Copies of this information may be obtained free of charge from the + 44(1223)336-033 or Email: [email protected] or www: http://www.ccdc.cam.ac.uk.

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)