title: A new structural alert for benzimidazoles: 2,6-dimethylphenyl substituents increase mutagenic potential and time-dependent CYP3A4 inhibition risk.
abstract: A series of 2-[(2,6)-dimethylphenyl]benzimidazole analogs displayed strong potential for mutagenicity following metabolic activation in either TA98 or TA100 Salmonella typhimurium strains. The number of revertants was significantly reduced by replacing the 2,6-dimethylphenyl group with a 2,6-dichlorophenyl moiety. Time-dependent CYP3A4 inhibition was also observed with a compound containing a 2-[(2,6)-dimethylphenyl] benzimidazole ring, implying risk for this scaffold to generate reactive metabolites.
authors.affiliation: Global Discovery Chemistry, Cambridge, MA 02139, USA.
authors.forename: Youngshin
authors.initials: Y
authors.lastname: Kwak
authors.forename: Gary
authors.initials: G
authors.lastname: Coppola
authors.forename: Cornelia J
authors.initials: CJ
authors.lastname: Forster
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gilmore
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Gong
authors.forename: Aaron
authors.initials: A
authors.lastname: Kanter
authors.forename: Alan
authors.initials: A
authors.lastname: Neubert
authors.forename: Bryan
authors.initials: B
authors.lastname: Stroup
authors.forename: Paul
authors.initials: P
authors.lastname: Szklennik
authors.forename: Susanne
authors.initials: S
authors.lastname: Glowienke
authors.forename: Pascal
authors.initials: P
authors.lastname: Stadelmann
authors.forename: Leslie
authors.initials: L
authors.lastname: Bell
authors.forename: Shari
authors.initials: S
authors.lastname: Bickford
authors.forename: Eric
authors.initials: E
authors.lastname: Gangl
authors.forename: Mithat
authors.initials: M
authors.lastname: Gunduz
authors.forename: Monish
authors.initials: M
authors.lastname: Jain
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhan
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
mesh_terms: D015766:Albendazole / Q000494:pharmacology; D000871:Anthelmintics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D009153:Mutagens; C031000:benzimidazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D015766:Albendazole