Synthesis of novel cyanopyridine compounds as potential EGFR inhibitors targeting A549 and PC3 cancer cell lines: In vitro, In vivo and ADME pharmacokinetics studies

Abstract

Developing new leads for fighting cancer is a challenge for organic and medicinal chemists; hence, new functionalized pyridines have been synthesized via several transformations, including new amide bond formation, cyclization, and hydrazone synthesis. Aminolysis of the ethyl ester 2 with benzylamine affords the benzyl amide 3. Hydrazinolysis of the ester 2 afforded hydrazide 4. Hydrazide 4 used as precursor to obtain new hydrazino- and cyclized derivatives 5–10. Moreover, new series of hydrazone derivatives 11–17 were synthesized by condensation 2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 4 with aromatic aldehydes and ketones. The synthesized compounds were subjected to cytotoxic screening against A549 and PC3 cells. Compounds 6 and 15 exhibited remarkable cytotoxic activities with IC50 values of 0.85 μM and 1.88 μM against A549 cells and IC50 values of 3.63 μM and 1.58 μM against PC-3 cells. Compounds 6, 8, and 15 exhibited promising EGFR inhibition with IC50 values of 42.6, 60.36, and 89.6 nM, respectively, compared to Erlotinib (93.7 %, IC50 = 78.6 nM). Moreover, compound 6 significantly activated apoptotic cell death in A549 cells, increasing the cell apoptosis by 76.7-fold (37.6 % in treated compared to 0.48 % for control) and arresting the cell cycle at S-phase by 32.56 % compared to control 24.03 %. Additionally, compound 6 caused tumor inhibition by 50.1 % of solid tumor in the SEC-bearing mice by interfering with EGFR enzymatic activity via considerable apoptosis-induction, which make it an attractive lead compound for the development of a chemotherapeutics to treat lung cancer.