Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors

Loredana Salerno; Emanuele Amata; Giuseppe Romeo; Agostino Marrazzo; Orazio Prezzavento; Giuseppe Floresta; Valeria Sorrenti; Ignazio Barbagallo; Antonio Rescifina; Valeria Pittalà

doi:10.1016/j.ejmech.2018.02.007

Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors

Eur J Med Chem. 2018 Mar 25:148:54-62. doi: 10.1016/j.ejmech.2018.02.007. Epub 2018 Feb 9.

Affiliations

¹ Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125, Catania, Italy.
² Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125, Catania, Italy; Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125, Catania, Italy.
³ Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125, Catania, Italy. Electronic address: arescifina@unict.it.
⁴ Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125, Catania, Italy. Electronic address: vpittala@unict.it.

PMID: 29454190
DOI: 10.1016/j.ejmech.2018.02.007

Abstract

Here we report the design, synthesis, and molecular modeling of new potent and selective imidazole-based HO-1 inhibitors in which the imidazole nucleus and the hydrophobic groups are linked by a phenylethanolic spacer. Most of the tested compounds showed a good inhibitor activity with IC₅₀ values in the low micromolar range, with two of them (1b and 1j) exhibiting also high selectivity toward HO-2. These results were obtained by the idea of potholing the entire volume of the principal hydrophobic western region with an appropriate ligand volume. Molecular modeling studies showed that these molecules bind to the HO-1 in the consolidated fashion where the imidazolyl moiety coordinates the heme iron while the aromatic groups are stabilized by hydrophobic interaction in the western region of the binding pocket. Finally, the synthesized compounds were analyzed for in silico ADME-Tox properties to establish oral drug-like behavior and showed satisfactory results.

Keywords: ADME-Toxicity; Docking studies; HO-1 imidazole inhibitors; Heme oxygenase-1 western region; In silico profiling.

MeSH terms

Animals
Binding Sites
Heme Oxygenase-1 / antagonists & inhibitors*
Hydrophobic and Hydrophilic Interactions
Imidazoles / chemistry*
Imidazoles / pharmacology
Inhibitory Concentration 50
Models, Molecular
Rats
Structure-Activity Relationship

Substances

Imidazoles
Heme Oxygenase-1