Design and Synthesis of Benzo-Spirocyclic Derivatives as Potent PARP-1 Inhibitors

ctive: In this study, we further explored the discovery of novel PARP-1 inhibitors based on previous studies. We designed and synthesized 6 compounds with different structures, which further enriched the structural types of novel PARP-1 inhibitors. Methods: Firstly, the structures of all target compounds were determined by ¹H NMR, ¹³C NMR, and high resolution MS. Next, the target compounds were evaluated for enzyme activity in vitro. Finally, ADMET prediction and molecular docking studies were used for experimental analysis. Results and Discussion: Compound (S10a) (IC₅₀ = 23.74 nM) was found to have PARP-1 enzyme inhibitory activity similar to Rucaparib (IC₅₀ = 23.88 nM). We also predicted the ADMET activity of all compounds, and their corresponding index values were similar to those of the reference drug Rucaparib. The molecular docking studies showed that compounds (X10a) and (S10a) could penetrate deep into the active pocket. Conclusions: Overall, based on the above analysis, the compounds reported in this paper have better research potential, and are expected to be the lead compounds for the discovery of novel PARP-1 inhibitors.