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Fourteen recent thiazolidine-2,4-diones bearing furan and/or thiophene heterocyclic rings have been designed, synthesized and assessed for their anticancer activities against four human tumor cell lines HepG2, A549, MCF-7 and HCT-116 targeting both VEGFR-2 and EGFR tyrosine kinases. Molecular design was carried out to investigate the binding mode of the proposed compounds with VEGFR-2 and EGFR receptors. HepG2 was the most susceptible cell line to the influence of our derivatives. Compounds 5g and 4g revealed the highest activities against HepG2 (IC 50 = 3.86 and 6.22 μM), A549 (IC 50 = 7.55 and 12.92 μM), MCF-7 (IC 50 = 10.65 and 10.66 μM) and HCT116 (IC 50 = 9.04 and 11.17 μM) tumor cell lines. Sorafenib (IC 50 = 4.00, 4.04, 5.58 and 5.05 μM) and elotinib (IC 50 = 7.73, 5.49, 8.20 and 13.91 μM) were used as reference standards. Furthermore, the most active cytotoxic compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were selected to assess their VEGFR-2 inhibitory effects. Derivatives 5g, 4g and 4f were observed to be the highest effective derivatives that inhibited VEGFR-2 at the submicromolar level (IC 50 = 0.080, 0.083 and 0.095 μM respectively) in comparison to sorafenib (IC 50 = 0.084 μM). As well, compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were additionally assessed for their inhibitory activities against mutant EGFR T790M . Compounds 5g and 4g could interfere with the EGFR T790M activity exhibiting stronger activities than elotinib with IC 50 = 0.14 and 0.23 μM respectively. Finally, our derivatives 4g, 5f and 5g showed a good in silico calculated ADMET profile. The obtained results showed that our compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFR T790M inhibitors with higher anticancer activity.

rsc advances

Design, synthesis, <i>in silico</i> docking, ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFR<sup>T790M</sup> tyrosine kinase inhibitors

Design, synthesis, in silico docking, ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFRT790M tyrosine kinase inhibitors

Design, synthesis, in silico docking, ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFR^T790M tyrosine kinase inhibitors