Design and synthesis of BMH-21-like quinazolinone derivatives as potential anti-cancer agents

•We developed a novel series of pyrido[2,1-b]quinazoline-6-carboxamide compounds (8a-t) designed specifically as RNA polymerase inhibitors.•Immunofluorescence analysis using the RPA 194 antibody revealed a significant decrease in RPA 194 expression.•Assessment of apoptosis-inducing activity confirmed that treatment with 8e led to apoptosis in up to 43 % of HepG2 cells.•Molecular docking studies further validated the effective interaction of derivatives 8e and 8l with a hexamer of the DNA double helix, showcasing favorable binding energies and modes. In the present study, a new series of quinazolin-4(3H)-one based compounds was designed, synthesized, and biologically evaluated as potential anticancer. The 11-oxo-11H-pyrido [2, 1-b] quinazoline-6-carboxylic acid 3a-c was synthesized as a precursor to prepare the pyridoquinazolinecarboxamides derivatives with different amines (7a-e). The molecular structures of these novel compounds were characterized through the analysis of various spectroscopic methods. Following that, the antiproliferative activity of synthesized compounds was evaluated against HepG2, MCF7, and HT-29 cancer cell lines. Compound 8e, with an IC50 of 2.07 µM, demonstrated higher potency than doxorubicin (IC50=2.15±0.021 µM) against HepG2 cancer cells, while the potency of 8l against HepG2 (liver cancer) was comparable to Dox. The effect of 8e and 8l on the destruction of Pol I subunit of RPA194 was evaluated; 8e and 8l exhibited a reduction in RPA 194 compared to the control. The 8e induces 43.1 % and 8l 37.6 % of HepG2 cell deaths, with doxorubicin being 52 %. Molecular modeling studies show the good binding free energies ranged from -8.32 to -11.7 kcal/mol with a hexamer of the DNA double helix. Accordingly, our findings imply that these derivatives serve as promising precursors for the design of potent anticancer agents.