Design and Pictet–Spengler enabled synthesis of carboxamide-substituted imidazo[1,2-a]quinoxalines as dual EGFR and tubulin targeting anticancer agents

2026-05-25

Joydeep Chatterjee

Gaurav Joshi *

Vibhu Jha *

Shivkanya M. Bhujbal *

Shivani Rathour

Sanjana Majumdar *

Muhammad Wahajuddin *

Prasad V. Bharatam

Raj Kumar *

DOI：10.1080/14756366.2026.2673744

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In this study, we report the Pictet–Spengler enabled synthesis of a series of eighteen carboxamide-substituted imidazo[1,2-a]quinoxaline derivatives (JRC-1-JRC-18) targeting epidermal growth factor receptor (EGFR) and tubulin. Compounds JRC-2 and JRC-6 exhibited potent antiproliferative effects against MCF-7 breast cancer cells, with IC50 values of 4.59 ± 0.23 µM and 4.01 ± 0.14 µM, respectively, outperforming erlotinib (IC50 = 9.39 ± 0.16 µM). In enzymatic assays, JRC-2 and JRC-6 inhibited wild-type EGFR with IC50 values of 294.45 nM and 383.90 nM, respectively. Notably, JRC-6 displayed microtubule-stabilising activity comparable to that of paclitaxel and induced ROS generation, mitochondrial membrane depolarisation, and G2/M phase cell cycle arrest. Molecular docking and molecular dynamics simulations confirmed stable binding of compounds at the EGFR ATP-binding site and the tubulin taxol-binding site.

Keywords:

EGFR kinase inhibition

tubulin polymerisation

dual-target anticancer agents

ROS-mediated apoptosis

molecular docking and dynamics

Design and Pictet–Spengler enabled synthesis of carboxamide-substituted imidazo[1,2-a]quinoxalines as dual EGFR and tubulin targeting anticancer agents

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