Design, Synthesis and in silico Studies of Pyrazoline-based Compounds as Anticancer Inhibitors

Abstract

In this work, few new pyrazoline derivatives Py1-Py5 were synthesised, characterised and their potential as EGFR kinase inhibitors was assessed. The target compounds were synthesized via Claisen-Schmidt condensation, followed by cyclization of the resulting chalcones using thiosemicarbazide. The anticipated chemical frameworks were confirmed by structural elucidation utilizing IR, ¹H NMR, ¹³C NMR and HRMS studies. All the derivatives showed substantial binding affinities in molecular docking analysis using AutoDock Vina against EGFR kinase (PDB ID: 3POZ). Compound Py3 exhibited the highest docking score (-10.2 kcal/mol), surpassing the co-crystallized ligand O3P (-10.0 kcal/mol) and demonstrated interactions with key EGFR inhibitory residues, including Lys50, Thr95, Met98 and Val131. ADMET projections indicated low toxicity, excellent pharmacokinetic characteristics and synthetic accessibility. Furthermore, compound Py2 had the lowest IC₅₀ value (44.47 µg/mL) in an in vitro cytotoxicity screening against MCF-7 breast cancer cells using the MTT test, indicating considerable activity. The structure-activity relationship analysis suggested that the presence of electron withdrawing substituents, especially chloro and nitro groups, enhances the cytotoxicity activity.