2-Propyl-3-Aminoquinazoline-4(3H)-one Derivatives as Potential Androgen Receptor Inhibitors: Synthesis and Cytotoxicity Against PC3 Cell Line via In Vitro and In Silico Studies

Abstract

Twenty-one novel quinazolin-4(3H)-one derivatives were synthesized and evaluated for their cytotoxic effects against the PC3 prostate cancer cell line. Structural characterization was performed using FTIR, NMR, and HRMS spectroscopy. Cytotoxicity assays revealed that compound 1 exhibited the highest potency (IC₅₀ = 4.29 ± 0.32 µM) and selectivity (SI = 20.1) against PC3 cells, surpassing the reference drug sorafenib. Compounds 10 and 11 also demonstrated significant selectivity (SI = 12.7 and 12.4, respectively), making them promising candidates for further investigation. Molecular docking studies confirmed strong binding affinities to the androgen receptor (AR), with compound 1 displaying the most favorable interaction (IFD Glide Score = −15.137 kcal/mol, MM-GBSA = –72.11 kcal/mol). MD simulations further supported the stability of compound 1 within the receptor binding site, highlighting key hydrogen bonding and π–π stacking interactions. ADME predictions indicated favorable pharmacokinetic properties, with all active compounds complying with drug-likeness criteria and exhibiting high oral absorption. Overall, these findings suggest that quinazolinone derivatives, particularly compound 1, hold significant potential as selective anticancer agents targeting prostate cancer.