Evaluation of Imidazole-Based Compounds as Heme Oxygenase-1 Inhibitors

Imidazole-based compounds previously synthesizedin our laboratory were selected and reconsideredas inhibitors of heme oxygenase-1 obtainedfrom the microsomal fractions of rat spleens. Mostof tested compounds were good inhibitors withIC50 values in the low micromolar range. Compoundswere also assayed on membrane-free full lengthrecombinant human heme oxygenase-1; alltested compounds were unable to interact withhuman heme oxygenase-1 at 100 micromolar concentrationswith the exception of compounds 11 and 13 thatinhibited the enzyme of 54% and 20%, respectively.The binding of the most active compound 11 withheme or heme-conjugated human heme oxygenase-1 was also examined by spectral analyses. Whenheme was not conjugated to human heme oxygenase-1, compound 11 caused changes in the hemespectrum only at concentration 50-fold (100 micromols)higher than that required to inhibit rat heme oxygenase-1; when heme was conjugated to humanheme oxygenase-1, compound 11 was able to forma heme-compound 11 complex also at low micromolarconcentrations. To obtain information on thebinding mode of the tested compounds withenzyme, docking studies and pharmacophore analysiswere performed. Template docking resultswere in agreement with experimental inhibitiondata and with a structure-based pharmacophoricmodel. These data may be exploitable to designnew OH-1 inhibitors.