title: Structure-Activity Relationships of 1,2-Disubstituted Benzimidazoles: Selective Inhibition of Heme Oxygenase-2 Activity.
abstract: Devising ways to up- or down-regulate heme oxygenase activity is attracting much interest as a strategy for the treatment of a variety of disorders. With a view of obtaining compounds that exhibit high potency and selectivity as inhibitors of the heme oxygenase-2 (HO-2) isozyme (constitutive) relative to the heme oxygenase-1 (HO-1) isozyme (inducible), several 1,2-disubstituted 1H-benzimidazoles were designed and synthesized. Specifically, analogues were synthesized in which the C2 substituent was the following: (1H-imidazol-1-yl)methyl, (N-morpholinyl)methyl, cyclopentylmethyl, cyclohexylmethyl, or (norborn-2-yl)methyl. Compounds with the cyclic system in the C2 substituent being a carbocyclic ring, especially cyclohexyl or norborn-2-yl, and the N1 substituent being a ring-substituted benzyl group, especially 4-chlorobenzyl or 4-bromobenzyl, best exhibited the target criteria of high potency and selectivity toward inhibition of HO-2. The new candidates should be useful pharmacological tools and may have therapeutic applications.
authors.affiliation: Department of Chemistry, Queen's University, Kingston, ON K7L 3N6 (Canada).
authors.forename: Xianqi
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON K7L 3N6 (Canada).
authors.forename: Dragic
authors.initials: D
authors.lastname: Vukomanovic
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON K7L 3N6 (Canada).
authors.forename: Kanji
authors.initials: K
authors.lastname: Nakatsu
authors.affiliation: Department of Chemistry, Queen's University, Kingston, ON K7L 3N6 (Canada). walter.szarek@chem.queensu.ca.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013154:Spleen / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2
keywords: 1,2-disubstituted 1H-benzimidazoles; heme oxygenases; inhibitors; structure-activity relationships