Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors.

Aim: The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities. Results: A new series of novel phthalazinone derivatives were designed and synthesized. Among these, B1 and B16 displayed more potent PARP-1 inhibitory activities than olaparib. B16 gave an IC50 value of 7.8 nM against PARP-1, and a PF50 value of 3.4 in the sensitizing effect assay. The in vivo pharmacokinetic properties evaluation showed B16 displayed insufficient oral exposure, and it was also not stable in rat blood. Conclusion: The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compound B16 was a valuable lead compound with significant in vitro efficacy, deserving further optimization to develop anticancer drug candidate.