Synthesis and SAR optimization of quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors

We have demonstrated that quinazolin-4(3H)-one, a nicotinamide (NI) mimic with PARP-1 inhibitory activity in the high micromolar range (IC50 = 5.75 μM) could be transformed into highly active derivatives with only marginal increase in molecular weight. Convenient one to two synthetic steps allowed us to explore extensive SAR at the 2-, and 5- through 8-positions of the quinazolin-4(3H)-one scaffold. Substitutions at the 2- and 8-positions were found to be most favorable for improved PARP-1 inhibition. The amino group at 8-position resulted in compound 22 with an IC50 value of 0.76 μM. Combination of the 8-amino substituent with an additional methyl substituent at the 2-position provided the most potent compound 31 [8-amino-2-methylquinazolin-4(3H)-one, IC50 = 0.4 μM] in the present study. Compound 31 inhibited the proliferation of Brca1-deficient cells with an IC50 value of 49.0 μM and displayed >10-fold selectivity over wild type counterparts. Binding models of these derivatives within the active site of PARP-1 have further supported the SAR data and will be useful for future lead optimization efforts.

The quinazolin-4(3H)-one starting PARP-1 inhibitor (IC50 = 5.75 μM) was systematically optimized to obtain 8-amino-2-methylquinazolin-4(3H)-one with an IC50 value of 0.4 μM. Binding model of this compound within the active site of PARP-1 rationalizes its potent activity.Figure optionsDownload as PowerPoint slideHighlights
► Poly(ADP-ribose) polymerase-1 is an attractive anticancer target.
► The 8-amino-2-methylquinazolin-4(3H)-one demonstrated submicromolar activity.
► Docking study provided molecular basis for potency.
► Potent compounds showed >10-fold selectivity to Brca1-deficient cell line.
► Cell-based activity was correlated well with compounds logP values.