Crystal structure, Hirshfeld, computational biomolecular investigations, and MTT assay studies of amino pyrimidine derivative as EGFR kinase domain inhibitor

Abstract

A nitrogen heterocyclic pyrimidine fused heterocyclic derivative 4-(4-Methoxyphenyl)-6-(2-phenylethyl)pyrimidin-2-amine (MPPPA), was synthesized and crystal structure is identified by single crystal XRD method. The asymmetric structure of MPPPA belongs to orthorhombic (Pna21) space group with unit cell parameters a = 14.6720(7) Å, b = 14.3922(6) Å, c = 7.6334(3) Å, α=β=γ= 90° and Z = 4. Two inter­molecular N3-H3A···N1i, N3-H3B···N2ii hydrogen bonds that fomrs R22(8) ring motifs in zigzag format that run along c-axis is noticed in supramolecular network of MPPPA crystal structure. The optimized structure of the compound is investigated using density functional theory (DFT). Energies of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) with other global reactivity parameters are computed. Further, surface map of molecular electrostatic potential (MEP) is determined using the electron density of the compound to recognize the reactivity region of our compound. To understand the supramolecular features, the close contacts of the molecular crystal of the complex is evaluated using Hirshfeld surface analysis by CrystalExplorer 17.5 program. Enrichment ratio is calculated to find the propensity of the intermolecular contacts in building the crystal packing. Bioactivity score, drug-likeness and ADMET properties of the compound is analysed to determine its potential bioactivity. In-silico molecular docking was performed to examine the EGFR inhibition of the MPPPA compound as a potential anticancer agent by docking with Crystal structure of EGFR kinase domain protein (PDB ID: 2J6M) using PyRx program. The MPPPA ligand is docked with 2J6M protein by three conventional N-H…O type hydrogen bonds, one C-H…O hydrogen bond, and various hydrophobic bonds with docking energy = -9.8 kcal/mol. Further, anticancer activity of MPPPA was investigated against lung cancer (A549), cervical cancer (HeLa) and liver cancer (Hep3b) cell lines and compared with activity of standard drug Gefitinib. In vitro results showed higher cytotoxicity of MPPPA with A549 cells and could be treated as lead molecule for lung cancer drug design.