Discovery of Anti‐Breast Cancer Thiophene Sulfonamide Derivatives: Design, Synthesis, Molecular Docking against EGFR, MM‐PBSA, MD Simulations, ADME/Tox, and in vitro Studies

With aim of developing the crucial pharmacophoric properties of the reported EGFR inhibitors (EGFRIs), a series of thiophene compounds having ethyl 5‐methylthiophene‐3‐carboxylate core were designed. The designed compounds were subjected to molecular docking studies that indicated the potentialities of compounds AP−A8, A9, A13 and A15 to be EGFRIs. Then, the MD simulations studies confirmed the stability and the correct binding of compound AP−A15 – EGFR complex at both energetic and conformational levels. Furthermore, in silico ADMET prediction revealed that the majority of the proposed compounds had drug‐like characteristics and have minimal toxicity and unfavourable side effects. The designed compounds were synthesized and there in vitro anticancer activity against the cancer cell line (MCF‐7) was measured. Ethyl 5‐methyl‐4‐phenyl‐2‐(2‐(4‐(thiophen‐2‐ylsulfonyl)piperazin‐1‐yl)acetamido)thiophene‐3‐carboxylate (AP−A15) was found to be most potent compound with EC50 values 3.5 μM, which was very close to Tamoxifen and Brigatinib. Majority compounds showed good to moderate cytotoxic activities ranging from 3.5 μM to 35.9 μM. Fifteen substituted thiophene derivatives were synthesized, characterization by various spectroscopic methods and screened for anticancer activity against MCF‐7 cell line by CCK‐8 assay. Compound AP−A15 found most activity against MCF‐7 cell line. In silico molecular docking studies, MD Simulations confirmed the perfect binding of compound AP‐A15 – EGFR complex.