title: Exploration of SAR for novel 2-benzylbenzimidazole analogs as inhibitor of transcription factor NF-κB.
abstract: A novel series of 2-benzylbenzimidazole analogs was designed, synthesized and investigated for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay. Among them, 4-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6e, >100% inhibition at 30 μM, IC50= 3.0 μM), 4-((5-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6j, 96% inhibition at 30 μM, IC50= 4.0 μM) and 2-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6k, 95% inhibition at 30 μM, IC50= 5.0 μM) showed strong inhibitory activity. The structure activity relationship confirmed that the substitution on benzimidazole ring A with hydrophobic cyclohexylmethoxy group at position 4 or 5 markedly enhances the activity. In addition, the hydrophilic hydrogen bonding donor group (OH) at position 2 or 4 on phenyl ring B connected with one methylene spacer to the benzimidazole ring is favorable for the inhibitory activity. However, hydrophobic (-OCH3and -Cl) groups on phenyl ring B decrease the activity.
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, 34134, South Korea.
authors.forename: PullaReddy
authors.initials: P
authors.lastname: Boggu
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, 34134, South Korea.
authors.forename: Eeda
authors.initials: E
authors.lastname: Venkateswararao
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, 34134, South Korea.
authors.forename: Manoj
authors.initials: M
authors.lastname: Manickam
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, 28644, South Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, 34134, South Korea. jungshh@cnu.ac.kr.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Jung
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D016328:NF-kappa B; C004453:bendazole
keywords: 2-Benzylbenzimidazole; LPS; NF-κB inhibitor