Synthesis, crystal, and Hirschfeld surface, DFT and molecular docking studies of 6-(3‑chloro-4-fluorophenyl)-4-ethoxy-2-(4-methoxyphenyl)quinazoline derivative

Abstract

The 4‑chloro-6-iodo-2-(4-methoxyphenyl)quinazoline 2 undergoes nucleophilic substitution with sodium ethoxide followed by the Suzuki–Miyaura reactions to afford novel 6-(3‑chloro-4-fluorophenyl)-4-ethoxy-2-(4-methoxyphenyl)quinazoline 4. Structural elucidation was carried out using a combination of spectroscopic (NMR, IR and MS) and single crystal X-ray diffraction (XRD) techniques. Compound 4 crystallizes in monoclinic space group C2/c with crystal parameters a = 28.116(4) Å, b = 7.2267(9) Å, c = 20.975(3) Å, β = 116.727(4)°, V = 3806.6(8) Å3 and Z = 8. The crystal packing is stabilized by intermolecular hydrogen bond, C–H⋯F, C–H⋯Cl, C–H⋯π, and π⋯π interactions. The halogen Cl⋯Cl contacts were found to be of the type I having the angles ϴ1 and ϴ2 = 154ᵒ. DFT analysis of the optimized geometry is in agreement with the solid phase results. The Hirshfeld surface was used to analyze the properties of the intermolecular interactions of 4. The energy-framework analysis reveals that π···π and C–H···π interactions energies are mainly dispersive and are the most important forces in the crystal structure. The in-silico evaluation of compounds 4 and vandetanib with the vascular endothelial growth factor receptor-2 (VEGFR-2) was carried out. Molecular docking results showed that 4 has the most favourable binding free energy (−9.39 kcal/mol) compared with that of vandetanib (−8.31 kcal/mol). The MD simulation results reveal there is a presence of hydrogen bonds between compound 4 and the VEGFR-2 protein.