Synthesis, Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies

Abstract

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).

Keywords: EGFR; VEGFR2; anticancer; docetaxel; methoxy quinazoline; synthesis.

Figure 1

Chemical structure for some quinazoline derivatives used as anticancer drugs, such as nolatrexed and Raltitrexed.

Figure 2

Reported quinazoline with GI₅₀ µg/mL [15] and designed quinazoline derivatives as antitumor compounds.

Scheme 1

Synthesis of new quinazoline derivatives 2–11.

Figure 3

Representative graph showing the most active compounds in every cell line, where Hela cell line columns are in blue, A549 cell line columns are in purple, and MDA cell line columns are in white.

Figure 4

The binding of M6 to EGFR ^L858R/T790M tyrosine kinase (PDB ID: 6S9B). (A) Surface representation for the binding mode of M6 (green), docetaxel (pink), and co-crystallized ligand compound 1 (white) to EGFR tyrosine kinase. Ribbon representation for the binding interaction of (B) M6 (green) and (C) docetaxel (pink) with EGFR tyrosine kinase. Hydrogen bonds are shown in green dashed lines.

Figure 5

(A) The backbone RMSD of M6-EGFR complex for 20 ns MD simulation. (B) Total number of molecular hydrogen bonds for the M6-EGFR complex over the simulation time.

Figure 6

The binding of M6 to VEGFR2 tyrosine kinase (PDB ID: 4ASD). (A) Surface representation for the binding mode of M6 (green), docetaxel (pink), and co-crystallized sorafenib (yellow) to VEGFR2 tyrosine kinase. Ribbon representation for the binding interaction of (B) M6 (green) and (C) docetaxel (pink) with VEGFR2 tyrosine kinase. Hydrogen bonds are shown in green dashed lines.

Figure 7

(A) The backbone RMSD of M6-VEGFR2 complex for 20 ns MD simulation. (B) Total number of molecular hydrogen bonds for the M6-VEGFR2 complex over the simulation time.