Heme oxygenase inhibition by 2-oxy-substituted 1-azolyl-4-phenylbutanes: effect of variation of the azole moiety. X-ray crystal structure of human heme oxygenase-1 in complex with 4-phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone.
A series of 1-azolyl-4-phenyl-2-butanones was designed and synthesized for the inhibition of heme oxygenases (heme oxygenase-1 and heme oxygenase-2). The replacement of imidazole by other azoles led to the discovery of novel 1H-1,2,4-triazole- and 1H-tetrazole-based inhibitors equipotent to a lead imidazole-based inhibitor. The inhibitors featuring 2H-tetrazole or 1H-1,2,3-triazole as the pharmacophore were less potent. Monosubstitution at position 2 or 4(5), or identical disubstitution at positions 4 and 5 of imidazole by a variety of electron-withdrawing or electron-donating, small or bulky groups, as well as the replacement of the traditional imidazole pharmacophore by an array of 3- or 5-substituted triazoles, identically 3,5-disubstituted triazoles, 5-substituted-1H- and 5-substituted-2H-tetrazoles proved to be detrimental to the inhibition of HO, with a few exceptions. The azole-dioxolanes and the azole-alcohols derived from the active azole-ketones were synthesized also, but these inhibitors were less active than the corresponding imidazole-based analogs. The first reported X-ray crystal structure of human heme oxygenase-1 in complex with a 1,2,4-triazole-based inhibitor, namely 4-phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone, was also determined. The inhibitor binds to the human heme oxygenase-1 distal pocket through the coordination of heme iron by the N4 in the triazole moiety, whereas the phenyl group is stabilized by hydrophobic interactions from residues within the binding pocket.
Roman
Gheorghe
G
Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
Rahman
Mona N
MN
Vukomanovic
Dragic
D
Jia
Zongchao
Z
Nakatsu
Kanji
K
Szarek
Walter A
WA
D018360:Crystallography, X-Ray; D004148:Dioxolanes / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000737:chemistry* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry*; D014965:X-Rays
D004148:Dioxolanes; D007093:Imidazoles; D013777:Tetrazoles; D014230:Triazoles; C045575:1,2,4-triazole; C045574:1H-tetrazole; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2