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Novel benzimidazole and quinazolinone inhibitors of the DNA repair enzyme Poly(ADP-ribose)polymerase

Lookup NU author(s): Professor Roger Griffin, Alex White, Kenneth Bowman, Professor Alan Calvert, Professor Nicola CurtinORCiD, Professor Herbie Newell, Emeritus Professor Bernard Golding


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Two novel series of inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP) were synthesized and evaluated for biological activity. In the benzimidazole-4-carboxamide series, the carbamoyl function was restricted into the putative biologically active conformation via an intramolecular hydrogen bond, while for quinazolin-4-[3H]-ones this was achieved by incorporation of the group into a heterocyclic ring. For both series of compounds, syntheses involved acylation of substituted anthranilic acid derivatives, followed by acid- or base-catalysed cyclization. 8-Hydroxyquinazolin-4-[3H]-ones were prepared from the corresponding 8-methoxy compounds by dealkylation with boron tribromide. PARP inhibitory activity was determined in permeabilized L1210 murine leukaemia cells, in comparison with the established inhibitor 3-hydroxybenzamide (IC50 = 8.3 μM). For both series, inhibitory activity varied with the nature of the 2-substituent, with benzimidazole-4-carboxamides proving approximately tenfold more potent than the previously prepared benzoxazole-4-carboxamides. 2-Arylbenzimidazoles were especially active, and 2-(4-methoxyphenyl)benzimidazole-4-carboxamide (IC50 = 60 nM) is the most potent PARP inhibitor reported to date. In the quinazolinone series, a 2-(4-nitrophenyl) substituent, and either an 8-methyl or 8-hydroxy group conferred potent inhibitory activity, with IC50 values of 0.13 and 0.23 μM, respectively, being observed.

Publication metadata

Author(s): Griffin, R.J., Srinivasan, S., White, A.W., Bowman, K., Calvert, A.H., Curtin, N.J., Newell, D.R., Golding, B.T.

Publication type: Article

Publication status: Published

Journal: Pharmaceutical Sciences

Year: 1996

Volume: 2

Issue: 1

Pages: 43-47

Print publication date: 01/01/1996

ISSN (print): 1356-6881

ISSN (electronic):