2. Academic Validation
  3. Ethanol-mediated one-pot synthesis of 3-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-ones as PDGFRA inhibitors

Ethanol-mediated one-pot synthesis of 3-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-ones as PDGFRA inhibitors

  • Eur J Med Chem. 2025 Jul 4:297:117914. doi: 10.1016/j.ejmech.2025.117914.
Mehul P Parmar 1,  Shreya Kashyap 2,  Disha P Vala 3,  Savan S Bhalodiya 4,  Chirag D Patel 5,  Joaquina Nogales 6,  Arijit Nandi 7,  Sourav Banerjee 8,  Hitendra M Patel 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120, Gujarat, India. Electronic address: mpparmar1997@gmail.com.
  • 2 Division of Cancer Research, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK. Electronic address: 2398415@dundee.ac.uk.
  • 3 Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120, Gujarat, India. Electronic address: dishuahir1999@gmail.com.
  • 4 Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120, Gujarat, India. Electronic address: sa1bhalodiya@gmail.com.
  • 5 Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120, Gujarat, India. Electronic address: chiragkumarp23@gmail.com.
  • 6 Division of Cancer Research, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK. Electronic address: jnogalesdiaz002@dundee.ac.uk.
  • 7 Department of Pharmacy, Sanaka Educational Trust Group of Institutions (SETGOI), Durgapur, West Bengal, 713212, India; Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Australia. Electronic address: arijitnandi57@gmail.com.
  • 8 Division of Cancer Research, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK. Electronic address: s.y.banerjee@dundee.ac.uk.
  • 9 Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120, Gujarat, India. Electronic address: hm_patel@spuvvn.edu.
PMID: 40633335 DOI: 10.1016/j.ejmech.2025.117914
Abstract

Establishing novel kinase inhibitors with Anticancer properties are key milestones in medicinal chemistry. To this end, the current work reports a new method for the synthesis of novel 3-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-ones with compound 4p exhibiting potent activity against type III receptor tyrosine kinase PDGFRA. These analogues were designed and prepared through a one-pot three-component reaction of 2-aminobenzimidazole with aryl-/heteryl-aldehydes and 5-phenyl-cyclohexane-1,3-dione in ethanol as a green and reusable solvent at reflux temperature. Being highly cost-effective and atom-efficient, this reaction gave a moderate to excellent yield up to 99 % in pure form without requiring any additional chromatographic technique. The key feature of designed route is achieving a 95 % yield of 4d during gram-scale synthesis. A kinase screening against a panel of 137 kinases revealed that 4p exhibited inhibitory activity against Platelet-derived growth factor receptor A with IC50 of 1.25 μM. The position of the methyl substituent on the imidazole ring of 4p is important for potency. In silico molecular docking, molecular dynamics simulations, and ADMET prediction reported that 4p and imatinib bind same at site of PDGFRA with potential brain bioavailability. High PDGFRA RNA expression correlates strongly with low- and high-grade glioma suggesting critical oncogenic properties in brain Cancer. Compound 4p potently kills all cells including primary patient-derived glioma cell lines suggesting a novel chemical backbone with drug-like potential with improved efficacy compared to clinical PDGFRA inhibitor imatinib.

Keywords

3-Phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-Ones; Gram-scale synthesis; Multiple bond formation; PDGFRA inhibitory activity; Reusable solvent.

Figures
Products