Thieno[2,3- b ]thiophene Derivatives as Potential EGFR WT and EGFRT 790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies.

Microwave-assisted synthesis and spectral analysis of certain novel derivatives of 3,4-diaminothieno[2,3- b ]thiophene-2,5-dicarbonitrile 1-7 were carried out. Compounds 1-7 were examined for cytotoxicity against MCF-7 and A549 cell lines using the quantitative MTT method, and gefitinib and erlotinib were used as reference standards. Compounds 1-7 were shown to be more active than erlotinib against the two cell lines tested. Compound 2 outperformed regular erlotinib by 4.42- and 4.12-fold in MCF-7 and A549 cells, respectively. The most cytotoxic compounds were subsequently studied for their suppression of kinase activity using the homogeneous time-resolved fluorescence assay versus epidermal growth factor receptor (EGFR ^WT ) and EGFR ^790M . With IC ₅₀ values of 0.28 ± 0.03 and 5.02 ± 0.19, compound 2 was demonstrated to be the most effective against both forms of EGFR. Furthermore, compound 2 also had the best antioxidant property, decreasing the radical scavenging activity by 78%. Molecular docking research, on the other hand, was carried out for the analyzed candidates ( 1-7 ) to study their mechanism of action as EGFR inhibitors. In silico absorption, distribution, metabolism, excretion, and toxicity tests were also performed to explain the physicochemical features of the examined derivatives.
Competing Interests: The authors declare no competing financial interest.
(© 2022 The Authors. Published by American Chemical Society.)