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

TY - JOUR

T1 - 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

AU - Parmar, Mehul P.

AU - Kashyap, Shreya

AU - Vala, Disha P.

AU - Bhalodiya, Savan S.

AU - Patel, Chirag D.

AU - Nogales, Joaquina

AU - Nandi, Arijit

AU - Banerjee, Sourav

AU - Patel, Hitendra M.

N1 - Publisher Copyright: © 2025 The Authors

PY - 2025/11/5

Y1 - 2025/11/5

N2 - 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.

AB - 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.

KW - 3-Phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-Ones

KW - Gram-scale synthesis

KW - Multiple bond formation

KW - PDGFRA inhibitory activity

KW - Reusable solvent

UR - https://www.scopus.com/pages/publications/105009933690

U2 - 10.1016/j.ejmech.2025.117914

DO - 10.1016/j.ejmech.2025.117914

M3 - Article

C2 - 40633335

SN - 0223-5234

VL - 297

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 117914

ER -