Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2<i>H</i>)‑one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase‑1 Inhibitors

Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3­(2<i>H</i>)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly­(ADP-ribose)­polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound <b>3</b> (DHBF-7-carboxamide; IC<sub>50</sub> = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (<b>36</b>, IC<sub>50</sub> = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene <b>58</b> (IC<sub>50</sub> = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds <b>66</b>–<b>68</b>, <b>70</b>, <b>72</b>, and <b>73</b>; IC<sub>50</sub> values from 0.718 to 0.079 μM). Compound <b>66</b> showed selective cytotoxicity in <i>BRCA</i>2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (<b>−</b>)<b>-13c</b>, <b>59</b>, and <b>65</b>) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.