Design, synthesis, and evaluation of 1H‐benzo[d]imidazole‐4‐carboxamide PARP‐1 inhibitors using different saturated nitrogen‐contained heterocycle as linker group

Abstract

AbstractPoly (ADP‐ribose) polymerase‐1 (PARP‐1) inhibitors have been successfully applied in the clinical treatment of various cancer. Side effects and drug resistant cases were reported, and more effective PARP‐1 inhibitors were required. However, studies on the AD site of PARP‐1 inhibitors are currently incomplete. Therefore, to synthesize more potential candidate PARP‐1 inhibitors and disclose some AD site SAR of the PARP‐1 inhibitors, herein, a series of 2‐phenyl‐benzimidazole‐4‐carboxamide derivatives using different saturated nitrogen‐contained heterocycles as linker group (6a‐6t) have been designed, synthesized, and evaluated PARP‐1 inhibitory activity and proliferation inhibitory against BRCA‐1 mutant MDA‐MB‐436 cell line in vitro. The results showed 6b (IC50 = 8.65 nM) exhibited the most PARP‐1 enzyme inhibitory activity comparable with Veliparib (IC50 = 15.54 nM) and Olaparib (IC50 = 2.77 nM); 6m exhibited the strongest MDA‐MB‐436 cell anti‐proliferation activity (IC50 = 25.36 ± 6.06 μM) comparable with Olaparib (IC50 = 23.89 ± 3.81 μM). The compounds 6b, 6r, and 6m could be potential candidates for effective PARP‐1 inhibitors and valuable for further optimization. The analysis of activity data also showed that the holistically anti‐proliferation activity of the 1,4‐diazepane group was about~twofold than that of the piperazine group. Meanwhile, the terminal 3‐methyl‐furanyl group exhibited the most robust PARP‐1 inhibitory and anti‐proliferation activity. It is hoped that the results could benefitable for further optimization of PARP‐1 inhibitors. Furthermore, we note that some compounds (6d,6g,6n,6p,6s) showed poor PARP‐1 inhibitory (>500 nM) but relatively good anti‐proliferation activity, which indicates the proliferation inhibitory mechanism against MDA‐MB‐436 cell line was worth investigating in‐depth.