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

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 = 3.86 and 6.22 μM), A549 (IC = 7.55 and 12.92 μM), MCF-7 (IC = 10.65 and 10.66 μM) and HCT116 (IC = 9.04 and 11.17 μM) tumor cell lines. Sorafenib (IC = 4.00, 4.04, 5.58 and 5.05 μM) and elotinib (IC = 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 = 0.080, 0.083 and 0.095 μM respectively) in comparison to sorafenib (IC = 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. Compounds 5g and 4g could interfere with the EGFR activity exhibiting stronger activities than elotinib with IC = 0.14 and 0.23 μM respectively. Finally, our derivatives 4g, 5f and 5g showed a good 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 inhibitors with higher anticancer activity.