Synthesis, investigation of the crystal structure, DFT and in silico medicinal potential of nicotinonitrile substituted quinazolindione as potential anticancer scaffold

Cancer is now regarded as one of the leading causes of death for people worldwide. Here, we have reported the synthesis of a new dihydroquinazoline derivative namely, 5-acetyl-4-(4-methoxyphenyl)-6-methyl-2-(((4-oxo-3,4-dihydro-quinazolin-2-yl)methyl)thio)nicotinonitrile (4). Its structure was characterised by IR and NMR and confirmed by XRD analysis. In the molecule (4), the dihydroquinazoline moiety is planar. The acetyl and phenyl substituents on the pyridine ring are rotated out of its plane to minimise steric interactions. In the crystal, a layered structure is formed by N—H···O, C—H···O, and C—H···N hydrogen bonds and π-stacking interactions. The large gap between the highest and lowest molecular orbitals indicates high stability. Moreover, the synthesised nicotinonitrile-substituted quinazolinone was screened for medicinal characteristics and drug-likeness estimates. The synthetic ligand was docked with three enzymes, including HER2 (PDB ID: 3WSQ), EGFR (PDB ID: 5WB7), and the extracellular domain of Tdp enzyme (PDB ID: 6N0D), where binding affinities of −8.02, −6.88, and −6.67 Kcal/mol, binding efficiencies of −0.24, −0.21, and −0.20 Kcal/mol and the inhibition constants 1.31, 9.07, and 12.84 µM against the target substrates Tdp1, EGFR, and HER2 protein were found, respectively. Molecular dynamics simulations validated the stability of the docked complexes.