title: Heme oxygenase inhibition by α-(1H-imidazol-1-yl)-ω-phenylalkanes: effect of introduction of heteroatoms in the alkyl linker.
abstract: Several α-(1H-imidazol-1-yl)-ω-phenylalkanes were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds were found to be potent and selective for the stress-induced isozyme HO-1, showing mostly weak activity toward the constitutive isozyme HO-2. The introduction of an oxygen atom in the alkyl linker produced analogues with decreased potency toward HO-1, whereas the presence of a sulfur atom in the linker gave rise to analogues with greater potency toward HO-1 than the carbon-containing analogues. The most potent compounds studied contained a five-atom linker between the imidazolyl and phenyl moieties, whereas the most HO-1-selective compounds contained a four-atom linker between these groups. The compounds with a five-atom linker containing a heteroatom (O or S) were found to be the most potent inhibitors of HO-2; 1-(N-benzylamino)-3-(1H-imidazol-1-yl)propane dihydrochloride, with a nitrogen atom in the linker, was found to be inactive.
authors.affiliation: Department of Chemistry, Queen's University, Kingston, ON, Canada.
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Vlahakis
authors.forename: Carmen
authors.initials: C
authors.lastname: Lazar
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Roman
authors.forename: Dragic
authors.initials: D
authors.lastname: Vukomanovic
authors.forename: Kanji
authors.initials: K
authors.lastname: Nakatsu
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D019800:Phenol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013455:Sulfur / Q000737:chemistry*
chemical_list: D000473:Alkanes; D007093:Imidazoles; D019800:Phenol; D013455:Sulfur; C029899:imidazole; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D010100:Oxygen