Heme oxygenase inhibition by 1-aryl-2-(1h-imidazol-1-yl/1h-1,2,4-triazol-1-yl)ethanones and their derivatives.
Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO-1 and HO-2). The majority of these were based on a four-carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1-aryl-2-(1H-imidazol-1-yl/1H-1,2,4-triazol-1-yl)ethanones and their derivatives. As regards HO-1 inhibition, the aromatic moieties yielding best results were found to be halogen-substituted residues such as 3-bromophenyl, 4-bromophenyl, and 3,4-dichlorophenyl, or hydrocarbon residues such as 2-naphthyl, 4-biphenyl, 4-benzylphenyl, and 4-(2-phenethyl)phenyl. Among the imidazole-ketones, five (36-39, and 44) were found to be very potent (IC(50)<5 muM) toward both isozymes. Relative to the imidazole-ketones, the series of corresponding triazole-ketones showed four compounds (54, 55, 61, and 62) having a selectivity index >50 in favor of HO-1. In the case of the azole-dioxolanes, two of them (80 and 85), each possessing a 2-naphthyl moiety, were found to be particularly potent and selective HO-1 inhibitors. Three non-carbonyl analogues (87, 89, and 91) of 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone were found to be good inhibitors of HO-1. For the first time in our studies, two azole-based inhibitors (37 and 39) were found to exhibit a modest selectivity index in favor of HO-2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.
Roman
Gheorghe
G
Department of Chemistry, Queen's University, Chernoff Hall, 90 Bader Lane, Kingston, ON K7L 3N6, Canada.
Vlahakis
Jason Z
JZ
Vukomanovic
Dragic
D
Nakatsu
Kanji
K
Szarek
Walter A
WA
D000818:Animals; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry*; D004148:Dioxolanes / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry
D001393:Azoles; D004148:Dioxolanes; D007093:Imidazoles; D014230:Triazoles; C045575:1,2,4-triazole; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2