Novel 5-bromoindole-2-carboxylic Acid Derivatives as EGFR Inhibitors: Synthesis, Docking Study, and Structure Activity Relationship

Abstract

Background: The indole backbone is encountered in a class of N-heterocyclic compounds with physiological and pharmacological effects such as anti-cancer, anti-diabetic, and anti-HIV. These compounds are becoming increasingly popular in organic, medicinal, and pharmaceutical research. Nitrogen compounds' hydrogen bonding, dipole-dipole interactions, hydrophobic effects, Van der Waals forces, and stacking interactions have increased their relevance in pharmaceutical chemistry due to their improved solubility. Indole derivatives, such as carbothioamide, oxadiazole, and triazole, have been reported to act as anti-cancer drugs due to their ability to disrupt the mitotic spindle and prevent human cancer cell proliferation, expansion, and invasion. background: Indole derivatives including carbothioamide, oxadiazole, and triazole have been reported to act as anti-cancer drugs due to their ability to disrupts the mitotic spindles and prevent proliferation, expansion, and invasion of human cancer cells. Objectives: To synthesize new 5-bromo-indole-2-carboxylic acid derivatives that function as EGFR tyrosine kinase inhibitors as deduced through molecular docking studies. objective: To synthesize new 5-bromo-indole-2-carboxylic acid derivatives that function as EGFR tyrosine kinase inhibitors as deduced through molecular docking studies. Methods: Different derivatives of indole (carbothioamide, oxadiazole, tetrahydro pyridazine-3,6-dione, and triazole) were synthesized and evaluated through different chemical, spectroscopic methods (IR, 1HNMR, 13CNMR, and MS) and assessed in silico and in vitro for their antiproliferative activities against A549, HepG2, and MCF-7 cancer cell lines. Results: According to molecular docking analyses, compounds 3a, 3b, 3f, and 7 exhibited the strongest EGFR tyrosine kinase domain binding energies. In comparison to erlotinib, which displayed some hepatotoxicity, all of the evaluated ligands displayed good in silico absorption levels, did not appear to be cytochrome P450 inhibitors, and were not hepatotoxic. The new indole derivatives were found to decrease cell growth of three different types of human cancer cell lines (HepG2, A549, and MCF-7), with compound 3a being the most powerful while still being cancer-specific. Cell cycle arrest and the activation of apoptosis were the results of compound 3a's inhibition of EGFR tyrosine kinase activity. Conclusion: The novel indole derivatives, compound 3a in particular, are promising anti-cancer agents which inhibit cell proliferation by inhibiting EGFR tyrosine kinase activity. conclusion: The novel indole derivatives, compound 3A in particular, are promising anti-cancer agents which inhibit cell proliferation by inhibiting the EGFR tyrosine kinase. other: NA

New Indole‐6‐Carboxylic Acid Derivatives as Multi‐Target Antiproliferative Agents: Synthesis, in Silico Studies, and Cytotoxicity Evaluation

“…Molecular similarity [21] The calculated chemical similarity between the newly synthesized compounds and the reference ligands Erlotinib and Sorafenib is shown in Supplementary Figure 9 and Supplementary Table 3. The assessment is based on various molecular properties, providing valuable insights into the structural and physicochemical characteristics of the compounds under investigation.…”