Synthesis and Evaluation of Salicylanilide Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

• Published in: Chemical biology & drug design Vol. 85; no. 3; pp. 280 - 289
• Main Authors: Hu, Minhua, Ye, Wenfeng, Li, Jiaming, Zhong, Guochen, He, Guangwei, Xu, Qinlong, Zhang, Yanchun
• Format: Journal Article
• Language: English
• Published: HOBOKEN Blackwell Publishing Ltd 01.03.2015; Wiley
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; antiproliferative effects; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Binding Sites; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; epidermal growth factor receptor inhibitor; Humans; Hydrogen Bonding; Life Sciences & Biomedicine; Molecular Docking Simulation; molecular modeling; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary; Quinazolines - chemistry; Quinazolines - metabolism; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; salicylanilide derivatives; Salicylanilides - chemistry; Salicylanilides - metabolism; Salicylanilides - pharmacology; Salicylanilides - toxicity; Science & Technology; Thermodynamics; molecular modeling; epidermal growth factor receptor inhibitor; BIOLOGICAL EVALUATION; antiproliferative effects; salicylanilide derivatives; CANCER; EGFR
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12383

Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC50 values of 10.4 ± 2.25 and 15.4 ± 2.33 nm, respectively, which were comparable to the positive control of gefitinib (IC50 = 12.1 ± 2.21 nm). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC50 values of 0.42 ± 0.43 μm and 0.57 ± 0.43 μm, which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ▵Gb = −25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well. Two series of novel salicylanilide derivatives were synthesized and their anti‐EGFR activity and anti‐proliferative were evaluated. Compound 12b was revealed to be a promising antitumor agent.