Design and Discovery of Phthalazinone-Based Potential PARP Inhibitors: Synthesis, Molecular Docking, ADMET Profiling, and In Vitro Evaluation

This study reports the design, synthesis, and biological evaluation of two novel phthalazinone-based carboxamides, N -(3-(3-methylbutanamido)phenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide and N -(4-(3-methylbutanamido)phenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide, as potential poly(ADP-ribose) polymerase-1 (PARP1) inhibitors. Structure-based molecular docking indicated favorable binding of both compounds within the PARP1 active site, with binding energies of − 8.5 and − 7.5 kcal·mol⁻¹, respectively. The stability and key interaction patterns of the more potent meta-substituted analogue were further validated by 250 ns molecular dynamics simulations. In silico ADMET profiling suggested acceptable drug-like properties for the synthesized compounds. Biochemical evaluation revealed enhanced inhibitory activity of the meta-substituted derivative against recombinant PARP1. Furthermore, both compounds exhibited cytotoxic effects in BRCA-mutant breast cancer cell lines, Capan-1 (BRCA2 c.5946delT) and MDA-MB-436 (BRCA1 c.5396 + 1G > A). Comparative analysis highlights the critical influence of the substituent position on the phenyl ring in modulating PARP1 binding stability and inhibitory activity. These findings identify the phthalazinone carboxamide scaffold as a promising platform for further structural optimization toward potent PARP1 inhibitors.