New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies.

Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC 50 values in the nanomolar range, compounds 8a , 5 were the most promising suppressors, producing IC 50 values of 2.31 and 3.05 nM compared to Olaparib with IC 50 of 4.40 nM. Compounds 4 , 10b , and 11b showed a mild decrease in the potency of the IC 50 range of 6.35-8.73 nM. Furthermore, compounds 4 , 5 , 8a , 10b , and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC 50 ; 2.57 µM, whereas the IC 50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4 , 5 , 8a , 10b , and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.