Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study

Abstract

A new series of 4,6-disubstituted 2-(4-(dimethylamino)styryl)quinoline 4a,b-9a,b was synthesized by the reaction of 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylic acids 3a,b with thiosemicarbazide, p-hydroxybenzaldehyde, ethylcyanoacetate, and 2,4-pentandione. In addition, the antitumour activity of all synthesized compounds 3a,b-9a,b was studied via MTT assay against two cancer cell lines (HepG2 and HCT116). Furthermore, epidermal growth factor receptor (EGFR) inhibition, using the most potent antitumour compounds, 3a, 3b, 4a, 4b, and 8a, was evaluated. The interpretation of the results showed clearly that the derivatives 3a, 4a, and 4b exhibited the highest antitumour activities against the tested cell lines HepG2 and HCT116 with IC₅₀ range of 7.7-14.2 µg/ml, in comparison with the reference drugs 5-fluorouracil (IC₅₀ = 7.9 and 5.3 µg/ml, respectively) and afatinib (IC₅₀ = 5.4 and 11.4 µg/ml, respectively). In vitro EGFR screening showed that compounds 3a, 3b, 4a, 4b, and 8a exhibited moderate inhibition towards EGFR with IC₅₀ values at micromolar levels (IC₅₀ range of 16.01-1.11 µM) compared with the reference drugs sorafenib (IC₅₀ = 1.14 µM) and erlotinib (IC₅₀ = 0.1 µM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase.

Keywords: EGFR kinase inhibitors; Styrylquinoline; antitumour; molecular docking; synthesis; thiadiazole.

Graphical abstract

Figure 1.

Reported EGFR inhibitors and antitumour agents, and design of the newly synthesized 2-styrylquinolines.

Scheme 1.

Synthesis of the designed 2-styryl-4-quinoline carboxylic acids, and 1,3,4-thiadiazoles 3a,b and 4a,b.

Scheme 2.

Synthesis of compounds 5a,b–9a,b.

Figure 2.

Relative viability of cells (%) against concentration of the newly synthesized compounds.

Figure 3.

Three-dimensional interactions of erlotinib (upper left panel), compounds 4b (lower left panel), and 3a (lower right panel) with the receptor pocket of EGFR kinase. Hydrogen bonds are shown as green line. Upper right panel shows superimposition of compounds 4b (green coloured) and 3a (yellow coloured) on erlotinib (red coloured) inside the pockets of the active site.