Recent Progress in the Research on Benzimidazole PARP-1 Inhibitors

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) is a multifunctional protein that plays an important role in DNA repair and genome integrity. PARP-1 inhibitors can be used as effective drugs not only to treat BRCA-1/2 deficient cancers because of the effect of synthetically lethal, but also to treat non-BRCA1/2 deficient tumours because of the effect of PARP capture. Therefore, the PARP inhibitors have become a focus of compelling research. Among these inhibitors, substituted benzimidazole derivatives were mainly concerned lead compounds. However, the commercial available benzimidazole PARP-1 inhibitors have some shortcomings such as serious toxicity in combination with chemotherapy drugs, in vivo cardiovascular side effects such as anemia. Therefore it’s crucial for scientists to explore more structure-activity relationships of the benzimidazole PARP-1 inhibitors and access safer and more effective PARP inhibitors. As the binding region of PARP-1 and the substrates is usually characterized as NI site and AD site, the modification of benzimidazoles mainly occurs on the benzimidazole skeleton (NI site), and the side chain of benzimidazole on 2-C position (AD site). Herein, the recent progresses of the researches of benzamides PARP inhibitors were introduced. We noticed that even though many efforts were taken to the modification of NI sites, there were still lacks of optimistic and impressive results. However, the structure-activity relationships of the modification of AD sites have not thoroughly discovered yet. We hope that enlightened by the previous researches, more researches of AD site should be occurred and more effective benzimidazole PARP-1 inhibitors could be designed, synthesized, and applied to clinics.