New poly(ADP-Ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-yl-pyrroline and -tetrahydropyridine Nitroxides and their Precursors

Kálai, Tamás and Balog, Mária and Szabó, Alíz and Gulyás, Gergely and Jekö, József and Sümegi, Balázs and Hideg, Kálmán (2009) New poly(ADP-Ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-yl-pyrroline and -tetrahydropyridine Nitroxides and their Precursors. J. Med. Chem., 52 (6). pp. 1619-1629. ISSN 0022-2623

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Abstract

4-Carboxamidobenzimidazoles were previously described as PARP inhibitor compounds. Here we report upon 4-carboxamido-1H-benzimidazoles substituted in the 2-position with nitroxides or their amine or hydroxylamine precursors. Among the new molecules, a highly active PARP inhibitor 4h (IC50 = 14 nM) was identified with antioxidant/radical scavenger activity. We concluded that in most cases sterically-hindered amines are better PARP inhibitors than their oxidized form and structural changes in the 2-substituted-4-carboxamido-1H-benzimidazoles, (such as N-substitution, or changing the position of the carboxamide group) was detrimental to PARP inhibition activity, but not on antioxidant activity. These results indicate the advantages in combining of an antioxidant nitroxide or nitroxide precursor with a PARP inhibitor molecule to decrease or eliminate the deleterious processes initiated by reactive oxygen and reactive nitrogen species (ROS and RNS). The radical scavenging capability of 4h was demonstrated by EPR study of urine collected after drug administration.

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