Synthesis, biological evaluation, and computational studies of some novel quinazoline derivatives as anticancer agents

Abstract

A series of quinazolinone derivatives (7a-7h) were synthesized as antiproliferative agents. All compounds, were synthesized through three steps method and structurally evaluated by FTIR, ¹H-NMR, ¹³CNMR and Mass spectroscopy. Their cytotoxic activities were assessed using MTT protocol against three humans cancerous (MCF-7, A549 and 5637) and normal (MRC-5) cell lines. In addition, molecular docking and simulation studies of the synthesized compounds were performed to assessment their orientation, interaction mode against EGFR as plausible mechanism of quinazoline compounds as anticancer agents. The synthesized compounds mostly showed moderate activity against the three studied cell lines. They also indicated an appropriate selectivity against tumorigenic and non-tumorigenic cell line. The molecular docking results also confirmed biological activity. Most of the compounds fulfilled Lipinski rule. Collectively, these compounds with further modification can be considered as potent antiproliferative agents.

Keywords: Anticancer agents; Computational Studies; Quinazoline; Synthesis.

Fig. 1

Several marketed and reported anticancer agents with quinazoline scaffold

Fig. 2

The summery schematic of the study

Fig. 3

Two conformations of co-crystal ligand (erlotinib) (AQ4) in the EGFR active site: The yellow and red color showed the crystal orientation and redocked conformation, respectively

Fig. 4

2D interactions of 7b (left) and 7e (right) with the residues in the binding site of receptor. (Vander waals: green, dark pink: pi-pi, light pink: pi-alkyl, purple: pi-sigma, orange: pi-cation, blue: halogen bond)

Fig. 5

2D interaction of erlotinib with the residues in the binding site of EGFR target. (Vander waals: green, dark pink: pi-pi, light pink: pi-alkyl, purple: pi-sigma, orange: pi-cation, blue: halogen bond)

Fig. 6

The RMSD plots for protein- ligand complexes during the simulation time

Fig. 7

RMSF distribution of residues during the simulation time

Fig. 8

Compactness changes of ligand-EGFR complexes analyzed by Rg parameters

Fig. 9

Number of hydrogen bonds between the EGFR and the selected ligands during the simulation time

Fig. 10

Synthesis path of designed quinazoline (7a–7h)