Benzimidazole Derivatives as Potential Dual Inhibitors for PARP-1 and DHODH

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

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.

MeSH terms

  • Benzimidazoles / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / drug effects*
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases