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 IC range of 7.7-14.2 µg/ml, in comparison with the reference drugs 5-fluorouracil (IC = 7.9 and 5.3 µg/ml, respectively) and afatinib (IC = 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 IC values at micromolar levels (IC range of 16.01-1.11 µM) compared with the reference drugs sorafenib (IC = 1.14 µM) and erlotinib (IC = 0.1 µM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase.

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New α,β-unsaturated ketones 4a,b; 5a–c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10–11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC50] ≅5.5–18.1 µΜ), in addition to significantly high ABTS•+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC50 values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC50 values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC50 = 1.28 µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.

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