Background: A significant number of heterocyclic compounds were developed as
poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Among them, 2-substituted benzimidazole-4-
carboxamide derivatives have gained importance in comparison with other heterocyclic systems.A new
library of benzimidazole 4-carboxamides were synthesised and screened for PARP-1 inhibitory activity.
Method: A facile and convergent synthesis of 2-[(4-substitutedcarbamoyl)piperidine-1-yl)methyl]-1Hbenzimidazole-
4-carboxamides (9a-m) was achieved from 2-(hydroxymethyl)-1H-benzimidazole-4-
carboxamide and piperidine-4-carboxamides (8a-m) using the Mitsunobu reaction. Standard PARP-1
inhibitors, 6(5H)-phenanthridinone and 4-amino-1,8-naphthalimide were procured from Sigma-Aldrich
and the data generated from plate reader was exported to the GraphPad Prism (Version 4) statistical
analysis software. The IC50 values were determined by plotting the concentration of compounds on xaxis
and optical density values on the y-axis. The crystal structure 2rcw.pdb of PARP was used for the
docking study. QSAR models were developed by using the heuristic method on CODESSA generated
conventional descriptors with the purpose of deriving structural requirements of these inhibitors. The
predictive ability of these compounds was verified by taking a set of five PARP inhibitors as a test set.
Results: Structures of the compounds (9a-m) were established on the basis of 1H-NMR, 13C-NMR and
mass spectral data. Overall, thirteen 2-substituted benzimidazole-4-carboxamide derivatives were synthesised
and screened for PARP-1 inhibitory studies. Interactions of compounds library as well as the
natural substrate NAD+ with the PARP active site residues were carefully analyzed and it was observed
that these inhibitors form a wide range of interactions. Correlation between the docking score and each
of their components with the PARP inhibitory activity of the compounds was studied.
Conclusion: Among 2-[(4-substitutedcarbamoyl)piperidine-1-yl)methyl]-1H-benzimidazole-4-carboxamides
(9a-m), compound 9a with isoquinolinyl group attached to piperidinyl-4-carboxamide group is highly
suitable for the PARP-1 inhibitory activity and compounds 9b, 9e, 9g and 9l have also shown good