Tabriz University of Medical Sciences Pharmaceutical Sciences 1735-403X 30 2 2024 04 01 Application of a Deep Eutectic Solvent for the Synthesis of Novel Imidazole-Containing Quinazoline Derivatives as Potent Cytotoxic Agents 215 228 10.34172/PS.2023.29 EN Fatemeh Azmian Moghadam https://orcid.org/0009-0005-4010-9478 Sara Dabirian Amin Ebrahimi Tavani Parisa Alipour Mohammad Mojabi Mehdi Evazalipour Fatemeh Yousefbeyk Saeed Ghasemi https://orcid.org/0000-0003-2007-2063 Journal Article 10.34172/PS.2023.29 2023 09 09 2023 12 11 Background: Drugs containing the 4-anilinoquinazolines scaffold play a critical role in cancer treatment by inhibiting protein kinases, especially tyrosine kinases. In this study, a novel series of 4-anilinoquinazoline derivatives were synthesized and evaluated as cytotoxic agents. Methods: All final compounds were synthesized using two methods, including a conventional approach using potassium iodide and dimethylformamide as well as a green method using a deep eutectic solvent (DES) comprising choline chloride: urea. The cytotoxicity was tested on the A431, HUVEC, and HU02 cell lines. To evaluate the binding pattern of the compounds with EGFR and VEGFR-2, a molecular docking investigation was performed. Finally, the wound healing assay was carried out to assess the potency of compounds in inhibiting cell migration. Results: The final reaction time was approximately 15-20 min with yields of 60-72% using DES, while the conventional method took 3 to 4 h to complete, with yields between 30% and 42%. Compounds 8k and 8l showed better cytotoxicity against both cell lines compared to vandetanib (IC50=0.11 µM and 0.26 µM on A431 and IC50=5.01 µM and 5.24 µM on HUVEC, respectively). Molecular docking studies revealed that compound 8k, which contained 3-methylaniline at the 4-position of the quinazoline core, showed efficient binding affinity to both EGFR and VEGFR-2. An essential hydrogen bond was formed between quinazoline N1 of 8k and the Met796 residue of EGFR with a docking score of -8.76 kcal/mol. The imidazole N3 of 8k interacted with the Cyc919 residue of VEGFR-2, forming a hydrogen bond with a docking score of -9.03 kcal/mol. Moreover, compound 8k exhibited the best inhibitory activity on cell migration and wound healing. Conclusion: DES significantly improved the time and yield of the final reactions. Compound 8k, which showed the best cytotoxicity and inhibitory activity on cell migration, could be a suitable candidate for further structural optimization.