2. Academic Validation
  3. Design, catalyst-free synthesis, DFT study and anticancer assessment of new 2,9-disubstituted purine-6-carboxamides

Design, catalyst-free synthesis, DFT study and anticancer assessment of new 2,9-disubstituted purine-6-carboxamides

  • Bioorg Chem. 2026 May:172:109529. doi: 10.1016/j.bioorg.2026.109529.
Joydeep Chatterjee 1,  Shivkanya M Bhujbal 2,  Gaurav Joshi 3,  Uttam Kumar Mishra 4,  Ashoke Sharon 4,  Muskan 1,  Shivam Singh 5,  Muhammad Wahajuddin 6,  Prasad V Bharatam 2,  Rajdeep Dalal 5,  Raj Kumar 7
Affiliations

Affiliations

  • 1 Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, India.
  • 2 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India.
  • 3 Institute of Cancer Therapeutics, School of Pharmacy & Medical Sciences, Faculty of Life Sciences, University of Bradford, BD71DP, United Kingdom; Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal (A Central) University, Srinagar 246174, Dist. Garhwal, Uttarakhand, India.
  • 4 Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
  • 5 Centre for Immunobiology and Immunotherapy, BRIC-Translational Health Science and Technology Institute, (An autonomous institute of the Dept of Biotechnology, Govt of India) Faridabad (Delhi NCR), Haryana 121001, India.
  • 6 Institute of Cancer Therapeutics, School of Pharmacy & Medical Sciences, Faculty of Life Sciences, University of Bradford, BD71DP, United Kingdom.
  • 7 Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, India. Electronic address: [email protected].
PMID: 41643510 DOI: 10.1016/j.bioorg.2026.109529
Abstract

A green, catalyst-free synthesis of seventeen new 2,9-disubstituted purine-6-carboxamides (5 and 6) designed as EGFR inhibitors in high yields (85-93%) was accomplished. DFT analysis revealed the formation of an energetically favorable oxazolidine transition state with a lower activation barrier compared to alternative pathways, supporting the experimentally observed selectivity. In vitro Anticancer activity against A549 lung Cancer cells demonstrated dose-dependent growth inhibition, with IC₅₀ values ranging from 4.35 to 22.1 μM, and compound 6E emerged as the most potent derivative. It exhibited superior activity compared to the reference drug erlotinib, with a cellular IC₅₀ of 4.35 μM vs 11.83 μM and an EGFR enzymatic IC₅₀ of 105.96 nM vs 218.47 nM, indicating approximately 2-fold enhanced potency. Flow cytometric analysis demonstrated that compound 6E significantly reduced p-PI3K levels, comparably to erlotinib, indicating effective suppression of EGFR-AKT downstream signaling at the cellular level. Mechanistic investigations demonstrated that 6E increased ROS generation, induced mitochondrial depolarisation, and promoted apoptotic cell death. Further, molecular docking and MD simulations of the 6E-EGFR complex highlighted key amino acid interactions, corroborating the observed in vitro EGFR inhibition.

Keywords

Anticancer; DFT; EGFR inhibition; Lung cancer; Purine-6-carboxamides; Synthesis.

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