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

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) angstrom, b = 7.2267(9) angstrom, c = 20.975(3) angstrom, beta = 116.727(4)degrees, V = 3806.6(8) angstrom(3) and Z = 8. The crystal packing is stabilized by intermolecular hydrogen bond, C-H center dot center dot center dot F, C-H center dot center dot center dot Cl, C-H center dot center dot center dot pi, and pi center dot center dot center dot pi interactions. The halogen Cl center dot center dot center dot Cl contacts were found to be of the type I having the angles Theta 1 and Theta 2 = 154 degrees. 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 pi center dot center dot center dot pi and C-H center dot center dot center dot pi 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. (c) 2022 Elsevier B.V. All rights reserved.