Heme Oxygenase Inhibition by α‐(1H‐Imidazol‐1‐yl)‐ω‐phenylalkanes: Effect of Introduction of Heteroatoms in the Alkyl Linker

Several α‐(1H‐imidazol‐1‐yl)‐ω‐phenylalkanes were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds were found to be potent and selective for the stress‐induced isozyme HO‐1, showing mostly weak activity toward the constitutive isozyme HO‐2. The introduction of an oxygen atom in the alkyl linker produced analogues with decreased potency toward HO‐1, whereas the presence of a sulfur atom in the linker gave rise to analogues with greater potency toward HO‐1 than the carbon‐containing analogues. The most potent compounds studied contained a five‐atom linker between the imidazolyl and phenyl moieties, whereas the most HO‐1‐selective compounds contained a four‐atom linker between these groups. The compounds with a five‐atom linker containing a heteroatom (O or S) were found to be the most potent inhibitors of HO‐2; 1‐(N‐benzylamino)‐3‐(1H‐imidazol‐1‐yl)propane dihydrochloride, with a nitrogen atom in the linker, was found to be inactive.