title: Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH.
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.
authors.affiliation: Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia. Electronic address: Iskandar.a@um.edu.my.
authors.forename: Iskandar
authors.initials: I
authors.lastname: Abdullah
authors.affiliation: 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.
authors.forename: Chin Fei
authors.initials: CF
authors.lastname: Chee
authors.affiliation: Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia.
authors.forename: Yean-Kee
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Aurigene Discovery Technologies (India) Ltd, India.
authors.forename: Siva Sanjeeva Rao
authors.initials: SSR
authors.lastname: Thunuguntla
authors.affiliation: Aurigene Discovery Technologies (India) Ltd, India.
authors.forename: K
authors.initials: K
authors.lastname: Satish Reddy
authors.affiliation: Aurigene Discovery Technologies (India) Ltd, India.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Nellore
authors.affiliation: Aurigene Discovery Technologies (India) Ltd, India.
authors.forename: Thomas
authors.initials: T
authors.lastname: Antony
authors.affiliation: Aurigene Discovery Technologies (India) Ltd, India.
authors.forename: Jitender
authors.initials: J
authors.lastname: Verma
authors.affiliation: Aurigene Discovery Technologies (Malaysia) Sdn. Bhd, Malaysia.
authors.forename: Kong Wai
authors.initials: KW
authors.lastname: Mun
authors.affiliation: 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.
authors.forename: Shatrah
authors.initials: S
authors.lastname: Othman
authors.affiliation: Aurigene Discovery Technologies (India) Ltd, India.
authors.forename: Hosahalli
authors.initials: H
authors.lastname: Subramanya
authors.affiliation: Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia.
authors.forename: Noorsaadah Abd
authors.initials: NA
authors.lastname: Rahman
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: Benzimidazole; DHODH; Dihydroorotate dehydrogenase; PARP; PARP-1; Poly (ADP-ribose) polymerase