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Bioorg Med Chem. 2015 Aug 1;23(15):4669-80. doi: 10.1016/j.bmc.2015.05.051. Epub 2015 Jun 5.

Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH.

Author information

1
Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia. Electronic address: Iskandar.a@um.edu.my.
2
Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia; Aurigene Discovery Technologies (Malaysia) Sdn. Bhd, Malaysia; School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia.
3
Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia.
4
Aurigene Discovery Technologies (India) Ltd, India.
5
Aurigene Discovery Technologies (Malaysia) Sdn. Bhd, Malaysia.
6
Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Malaysia.

Abstract

Poly (ADP-ribose) polymerases (PARPs) play diverse roles in various cellular processes that involve DNA repair and programmed cell death. Amongst these polymerases is PARP-1 which is the key DNA damage-sensing enzyme that acts as an initiator for the DNA repair mechanism. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the pyrimidine biosynthetic pathway which is an important target for anti-hyperproliferative and anti-inflammatory drug design. Since these enzymes share a common role in the DNA replication and repair mechanisms, it may be beneficial to target both PARP-1 and DHODH in attempts to design new anti-cancer agents. Benzimidazole derivatives have shown a wide variety of pharmacological activities including PARP and DHODH inhibition. We hereby report the design, synthesis and bioactivities of a series of benzimidazole derivatives as inhibitors of both the PARP-1 and DHODH enzymes.

KEYWORDS:

Benzimidazole; DHODH; Dihydroorotate dehydrogenase; PARP; PARP-1; Poly (ADP-ribose) polymerase

PMID:
26088338
DOI:
10.1016/j.bmc.2015.05.051
[Indexed for MEDLINE]

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