1-Oxo-3,4-dihydroisoquinoline-4-carboxamides as novel druglike inhibitors of poly(ADP-ribose) polymerase (PARP) with favourable ADME characteristics

A novel 3,4-dihydroisoquinol-1-one-4-carboxamide scaffold was designed as the basis for development of inhibitors poly(ADP-ribose) polymerase (PARP). Synthesis 3,4-dihydroisoquinol-1-one-4-carboxylic acids achieved using previously developed protocol based on modified Castagnoli-Cushman reaction homophthalic anhydrides and 1,3,5-triazinanes formaldimine synthetic equivalents. Employment 2,4-dimethoxy groups nitrogen atom latter allowed preparation 2,3-unsubatituted 3,4-dihydroquinolone core building blocks. Iterative synthesis in vitro biological testing amides resulting from amidation these carboxylic not only drawing important structure-activity generalisations (corroborated by silico docking simulation) but also identification lead compound, 4-([1,4'-bipiperidine]-1'-carbonyl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one, candidate further preclinical development. The compound well its des-fluoro analog were compared to approved PARP1 inhibitor, anticancer drug Olaparib, terms their molecular characteristics defining druglikeness experimentally determined ADME parameters. newly series demonstrated clear advantages over Olaparib weight, hydrophilicity, human liver microsomal plasma stability protein binding. Further investigation is highly warranted.