ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

In vitro and in silico evaluation of 4'-hydroxy-[1,1'-biphenyl]-4-carbohydrazide Schiff base and oxadiazole derivatives targeting EGFR allosteric site

Wurood A. Shihab, Ammar A. Razzak Mahmood, Lubna H. Tahtamouni, Mai F. AlSakhen, Sana I. Kanaan, Khaled M. Saleh, and Salem R. Yasin

Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab-Al-Mouadam, Baghdad, Iraq

E-mail: amar.mahmoud@copharm.uobaghdad.edu.iq

Received: 17 November 2023  Accepted: 7 August 2024

Abstract:

Inhibition of EGFR tyrosine kinase (TK) activity is considered a promising therapeutic strategy for cancer treatment. Type I and II EGFR TK inhibitors bind the ATP-binding site, while type III and IV inhibitors target an allosterically sensitive pocket proximal to the ATP-binding site present in a variety of kinases. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR tyrosine kinase allosteric site inhibitors based on molecular docking studies. A novel series of 4'-hydroxy-[1,1'-biphenyl]-4-carbohydrazide derivatives (W3–W15) were synthesized and characterized using infrared, ¹HNMR, and ¹³CNMR spectroscopy, and high-resolution mass spectrometry. Compound W4 had a favorable pharmacophore-fit score suggesting that it may have biological activity similar to the reference 6DUK (EGFR with bound allosteric inhibitor). Compound W4 exhibited a favorable ΔG score against EGFR TK allosteric site indicating a high likelihood of compound-receptor complex formation, and it was predicted to be non-carcinogenic and non-irritant. Compounds W3–W7 demonstrated selective cytotoxicity towards the A549 lung cancer cell line as compared to the other two cell lines investigated (HCT-116 colorectal and HeLa cervical cancer cells). Compound W4’s IC₅₀ value against A549 cancer cells (0.4 µM) was 20-fold lower than Erlotinib’s (7.3 µM). Finally, compound W4 targeted EGFR TK in the A549 cell line, causing cell cycle arrest at the G2/M phase and activating the extrinsic apoptotic pathway. In conclusion, compound W4 is a promising EGFR tyrosine kinase allosteric inhibitor that is worthy of further investigation.

Graphical Abstract

Keywords: Biphenyl scaffold; Cytotoxicity; EGFR tyrosine kinase; Allosteric site inhibitors; Molecular docking

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03648-3

Chemical Papers 78 (14) 7951–7971 (2024)