Synthesis and evaluation of imidazole-dioxolane compounds as selective heme oxygenase inhibitors: effect of substituents at the 4-position of the dioxolane ring.
Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include a series of substituted thiophenol and substituted phenol derivatives of (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[(phenylsulfanyl)methyl]-1,3-dioxolane hydrochloride (3), in addition to smaller functionalized derivatives, continue our structure-activity studies by exploration of the aminothiophenol region ('northeastern region') in our original target structure azalanstat (1). In vitro, most of the compounds in this series were found to be highly potent inhibitors of the stress-induced isozyme HO-1 and the constitutive isozyme HO-2, showing only moderate selectivity for HO-1. Nevertheless, a few of the compounds displayed higher selectivity toward HO-1. None of the compounds having a larger appendage in the northeastern region were inhibitors of CYP2E1, whereas a compound having a relatively small fluorine substituent in this region did inhibit CYP2E1; all of the compounds tested exhibited high inhibitory potency against CYP3A1/3A2.
Vlahakis
Jason Z
JZ
Department of Chemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Hum
Maaike
M
Rahman
Mona N
MN
Jia
Zongchao
Z
Nakatsu
Kanji
K
Szarek
Walter A
WA
D004148:Dioxolanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization
D004148:Dioxolanes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D006419:Heme Oxygenase (Decyclizing)