Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors

Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t(1/2) of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.

Automated summary

Two series of novel compounds with PARP-1 inhibition activity were designed and synthesized, among which compound II-4 showed high PARP-1 inhibition activity and anti-proliferative activity, indicating its potential as a lead compound for the development of PARP-1 inhibitors.