Aim: A new series of 3,4-dihydronaphthalen-1(2 h)-ylidene)hydrazineylidene)-5-substituted thiazolidin-4-one derivatives were designed and synthesized.
Results & methodology: The new compounds were screened for in vitro antitumor activity against Hela cancer cell line. The compounds 7b, 7 h, and 7i produced more potent cytotoxicity than doxorubicin with IC50 values of 1.83 ± 0.1, 2.54 ± 0.14, 2.75 ± 0.15, and 3.63 ± 0.2 μM, respectively. They also showed a promising safety profile against WI-38 normal cells. In addition, compound 7b produced a promising multi-kinase inhibition against EGFR (WT) while being very selective toward the mutant forms (L858R and T790M) with IC50 values of 0.099 ± 0.006, 0.064 ± 0.006, and 0.026 ± 0.007 μM, respectively, in comparison to gefitinib and osimertinib. A study of the cell cycle in Hela cells showed that 7b arrests cell cycle in the pre-G1 phase and causes early and late apoptosis. Eventually, the molecular docking results showed that 7b had good-binding interactions with EGFRWT, EGFRL858R, and EGFRT790M.
Conclusion: Compound 7b was predicted to have promising oral absorption, good drug-likeness, and low toxicity risks in humans. Moreover, MD simulations confirmed the stable complexes of 7b with EGFRWT, EGFRL858R, and EGFRT790M (with RMSD 0.12-0.35 nm, RMSF 0.2-0.55 nm, SASA 140-150, and Rg 1.80-2.00 nm).
Keywords: EGFR inhibition; Thiazolidin-4-ones; cell cycle; cervical cancer; molecular docking; molecular dynamic.