Growing the molecular architecture of imidazole-like ligands in HO-1 complexes

Abstract

Up-regulation of HO-1 had been frequently reported in different cases and types of human malignancies. Since poor clinical outcomes are reported in these cases, this enzyme's inhibition is considered a valuable and proven anticancer approach. To identify novel HO-1 inhibitors suitable for drug development, we report a structure-guided fragment-based approach to identify new lead compounds. Different parts of the selected molecules were analyzed, and the different series of novel compounds were virtually evaluated. The growing experiments of the classical HO-1 inhibitors structure led us to different hit-compounds. A synthetic pathway for six selected molecules was designed, and the compounds were synthesized. The biological activity revealed that molecules 10 and 12 inhibit the HO-1 activity with an IC₅₀ of 1.01 and 0.90 μM, respectively. This study suggested that our growing approach was successful, and these results are ongoing for further development.

Keywords: Fragment growing; Fragment-based ligand design; HO-1 inhibitors; Heme Oxygenase; Imidazole; Structure-based drug design.