Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers

• Published in: Bioorganic chemistry Vol. 105; p. 104358
• Main Authors: Amin, Noha H., Elsaadi, Mohammed T., Zaki, Shimaa S., Abdel-Rahman, Hamdy M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2020
• Subjects: A549 Cells; Aniline Compounds - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antitumor; Apoptosis - drug effects; Benzenesulfonamides; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; EGFR inhibition; ErbB Receptors - antagonists & inhibitors; Humans; Molecular docking; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Quinazoline; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Styryl; Sulfonamide; Sulfonamides - chemistry; Styryl; Sulfonamide; EGFR inhibition; NCI; Antitumor; SEM; Quinazoline; RTKs; MTT; Molecular docking; EGFR
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104358

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•Styrylquinazolines conjugated with aniline or sulfonamides targeting EGFR were synthesized.•Anticancer screening, MTT, EGFR/ A549 anti-proliferative activity were evaluated.•Cell cycle studies were demonstrated.•ADMET and EGFR Molecular docking studies were performed.
Herein, we report the synthesis of novel 2-substituted styrylquinazolines conjugated with aniline or sulfonamide moieties, anticipated to act as potent anticancer therapeutic agents through preferential EGFR inhibition. In doing so, all the synthesized compounds were screened for their in vitro anticancer activities (nine subpanels) at the National Cancer Institute (NCI), USA. The resulting two most active anticancer compounds (7b and 8c) were then chemically manipulated to investigate feasible derivatives (12a-e and 15a-d). MTT cytotoxicity, in vitro cell free EGFR and anti-proliferative activity against EGFR/ A549 cell line evaluation for the most active broadly spectrum candidates (7a/b, 8c/e, 12b and 15d) was conducted. Promising results were obtained for the styrylquinazoline-benzenesulfonamide derivative 8c (IC50 = 8.62 µM, 0.190 µM and = 79.25%), if compared to lapatanib (IC50 = 11.98 µM, 0.190 µM, and 79.25%), respectively. Moreover, its apoptotic induction potential was studied through cell cycle analysis, Annexin-V and caspase-3 activation assays. Results showed a clear cell arrest at G2/M phase, a late apoptotic increase (76 folds) and a fruitful caspase-3 expression change (8 folds), compared to the control. Finally, molecular docking studies of compounds 7a/b, 8c/e, 12b and 15d revealed proper fitting into the active site of EGFR with a low binding energy score for compound 8c (−13.19 Kcal/mole), compared to lapatanib (−14.54 Kcal/mole).