1-trityl-4-nitroimidazole.
X-ray analysis confirmed the configuration of the title N1-alkylated C4-nitroimidazole inhibitor. The plane of the imidazole ring, sitting on an axis of the trityl propeller, bisects the angle between two phenyl rings, while the nitro group extends over the third. Modeling of the interactions between the cytochrome P450 and the title compound (C22H17N3O2) has been performed on the basis of the crystal structures of 1-trityl-4-nitroimidazole and bacterial cytochrome P450BM-3. The replacements and deletions in the sequence of the latter has been performed to match mammalian cytochrome P450-IIIA1. The modeling explained why inhibitors with a C4-substituted imidazole ring showed lower effectivity than those without substituents, as an additional group of atoms at C4 prevents close interactions of the imidazole ring with the heme Fe atom.
Skrzypczak-Jankun
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E
Department of Chemistry, University of Toledo, OH 43606, USA.
Kurumbail
R G
RG
D000935:Antifungal Agents / Q000378:metabolism*; D003022:Clotrimazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D009593:Nitroimidazoles / Q000378:metabolism*; D014320:Triphenylmethyl Compounds / Q000378:metabolism*
C098803:1-trityl-4-nitroimidazole; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D009593:Nitroimidazoles; D014320:Triphenylmethyl Compounds; D003022:Clotrimazole