Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI50 values ranging from 0.70 mM to 1.20 mM, compared to doxorubicin GI50 value = 1.10 mM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC50 values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC50 = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC50 values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC50 = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

A series of novel thiazolidine-4-one derivatives were synthesized and evaluated for their antiproliferative, inhibitory, and apoptotic activities. Compounds 5d, 5e, and 5f exhibited the strongest antiproliferative activity and showed potent inhibition against CDK2 and EGFR. The compounds were also found to increase the activity of caspases and cytochrome C levels. Molecular docking studies confirmed the strong binding affinity of compound 5h to the active sites of CDK2 and EGFR.