Starting from the hypothesis that the linker portion of the
Starting from the hypothesis that the linker portion of the inhibitor molecules does not necessarily require the presence of an alcohol/ether or a carbonyl group, the same research group performed another scaffold hopping analysis, obtaining 1500 new compounds as potentially active HO-1 inhibitors . The molecules were again obtained with Spark and evaluated by the superposition on the previously reported 3D-QSAR model . The bioisosteric replacement was performed as showed in Fig. 7. The attention was mainly focused on the bromine XMD17-109 (Series 1) and on the aromatic substituents that interact with the western region (Series 2 and 3). A simple alkyl/aryl tether was used as a linker among all the series, and the imidazole moiety was maintained due to its important function as the anchoring point to the heme/enzyme complex. Accordingly with the 3D-QSAR evaluation, the new molecules have the appropriate chemical structure for the inhibition of HO-1 with predicted potencies that reaches an IC50 value of 0.1 μM; the most potent compounds belonging to the three series are reported in Table 10 (the full list of compounds is reported in the original paper ).
An analysis of these results confirmed the hypothesis that a simple alkyl/aryl chain could be used as a linker between the two-fundamental moieties of the “classical” HO-1 inhibitor, without affecting the potency. To verify this assumption and the predictive capabilities of the 3D-QSAR model, the authors synthesized two of the predicted derivatives (Fig. 8), compounds 23 (pIC50 = 6.0) and 24 (pIC50 = 4.5). The first for its high potency and the second to verify the predictive range. The two compounds were synthesized in a two-step fashion, and the subsequent biological evaluation against HO-1 showed an IC50 of 0.9 and 54 μM, respectively, confirming the authors’ hypothesis.
Potential therapeutic application for HO-1 inhibitors
Conclusion and perspectives Fifty years after the identification of HO family, considerable information has been gained about expression, signaling, and in vitro and in vivo functions of these enzymes. Starting from the new century, the availability of imidazole-based inhibitors as well as of HO-1 knockout mice drove important advancement in the understanding of the role of HO-1. In the last decade, medicinal chemistry efforts were extensively addressed to the development of potent and selective HO-1 inhibitors. These efforts were intensely reinforced by computational studies. The purpose of this review is to highlight the recent advances in the development of new selective HO-1 and HO-2 inhibitors and their potential application in several diseases, according to discoveries achieved during the last six years (2013–2018). Regarding HO-2 inhibition, among imidazole derivatives a crucial feature which discriminates between HO-1 and HO-2 inhibition is the presence of a five element linker coupled with an appropriate aryl moiety such as 5-chlorobenzothiazole. Besides, 1-H-benzimidazole derivatives devoid of an imidazole residue, variously substituted at N1 and C2 positions, emerged as selective inhibitors. The best substitutions for maintaining the selectivity and high power at HO-2 are the introduction of a C1 carbocyclic ring and a benzyl group substituted with N1. Since the structure of the enzyme complexed with a selective HO-2 inhibitor has not yet been solved, information on the binding mode of inhibitors with HO-2 are not currently available. Therefore, one of these novel HO-2 selective inhibitors may be a good candidate for crystallographic/computational studies. Based on the demonstrated importance of HO-1 in the pathophysiology and therapy of various diseases, including neonatal jaundice, cancer, and neurodegenerative diseases, particularly AD, the possible application of some of the novel described HO-1 inhibitors in these pathologies was tested. Notably, in several cancer cells, including breast, pancreas, melanoma, neuroblastoma, and CML, selected HO-1 inhibitors were able to reduce cell viability, confirming the potential application in cancer therapy. However, these results were obtained at high doses (medium micromolar range); therefore an increase of antitumor potency of HO-1 inhibitors is desirable. Overall, a combination of HO-1 inhibition with conventional chemotherapy has given good results in other type of tumors producing synergistic effects and/or overcoming drug-resistance. New to the field of HO-1 inhibitors are hybrid compounds obtained from a combination of an IM-like portion and an aryloxybutylimidazol moiety in the same molecule, which are active in an in vitro model of CML, and which could thus open new frontiers in the treatment of cancer.