Design, synthesis, and evaluation of quinazolinone derivatives as potential BRD4 BD1 agents

The quinazolinone core serves as a foundational structure, displaying substantial anti-tumor activity. BRD4 BD1 inhibitors are of great importance as they can effectively disrupt cancer cell proliferation and gene expression. Therefore, utilizing scaffold—hopping strategy based on pharmacophore, we have effectively synthesized a collection of BRD4 BD1 inhibitors featuring the quinazolinone core. The synthesized compounds were analyzed via 1HNMR, 13CNMR, HRMS and HPLC techniques. With the aid of screening with computer assistance and evaluations of antitumor activity, most of these compounds have exhibited notable inhibitory impacts on an array of cancer cell lines. In particular, compound 2b (IC50 = 3.71 μM against MCF-7 cells) has stood out with its exceptional anticancer activity, which is characterized by inducing G2 to M phase cell cycle stagnation and cellular fluorescence staining. Molecular docking studies were conducted to predict the interaction of compound 2b with the active sites of BRD4 BD1. Molecular docking simulations indicate that the tert-butyl group on the terminal phenyl ring of compound 2b can form nonpolar hydrophobic interactions with the BD1-specific residue Ile-146 and residues at the bottom of the binding pocket, thereby significantly enhancing its binding affinity for BD1. Quinazolinone-based compound in Y-shape anchors amino acids for potent anti-tumor action as BRD4 BD1 inhibitor.