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  • Iodoacetyl-LC-Biotin The central region of Azalanstat

    2021-11-11

    The central region of Azalanstat can be substituted with connecting alkyl chains of different nature and length. Interesting results were given by compounds with a four or five Iodoacetyl-LC-Biotin chain, incorporating heteroatoms, such as oxygen (Fig. 2, compound 4) or sulfur, and different functional groups such as a dioxolane ring (Fig. 2, compounds 1 and 2), a ketone (Fig. 2, compounds 3 and 5) or an alcohol function (Fig. 2, compound 6) [[49], [50], [51], [52]]. Elimination of the chiral center in the central region of Azalanstat does not alter the activity but allows simplifying the structure. The western region is one of the main feature responsible for binding to HO-1 and represents the most diverse area among HO-1 inhibitors reported so far. This part of HO-1 inhibitors, by giving additional interaction with the distal hydrophobic pocket of the enzyme, is able to further stabilize the binding and improve the activity. In light of the high flexibility of this pocket, as demonstrated by crystallographic studies, a wide variety of hydrophobic groups (heterocycles, aryl, adamantyl, etc.) of different sizes can be allocated (Fig. 2, compounds 5 and 7) [53]. These SAR studies along with X-ray crystallography studies (reviewed in section 3) provided valuable information about the mode of binding of these compounds to HO-1 and elucidated the main structural features required. The literature concerning HO-1 inhibitors has been recently reviewed and, hereafter, we will illustrate the most relevant achievements of the last years (2013–2018) towards the discovery of potent and selective HO-1 inhibitors [26,37]. Another research group active in the field of HO-1 inhibitors is based at the University of Catania. In recent years, this team has synthesized a large number of imidazole-based compounds, identifying potent and selective HO-1 inhibitors vs HO-2 or vice versa. The group took a cue from in-house synthesized NOS inhibitors sharing with HO-1 inhibitors similar key functional groups, namely an imidazole nucleus and an arylic portion linked through a central spacer, such as an ethanol, an ethanone, an alkylen or an alkoxy chain [50,54]. Thus, in 2012, based on a virtual screening on an in-house collection of NOS inhibitors, the team started a research program aimed at identifying selective HO-1 inhibitors [50]. From this screening, a small group of compounds showed interesting HO-1 activity, combined with low or no effect on NOS or CYP450 (Fig. 2, compound 4 and Fig. 3, derivatives 7a–d. Among these, 1-[4-(3-bromophenoxy)butyl]-1H-imidazole 4 (Fig. 2), showed inhibition potency in the low micromolar order (IC50 HO-1 = 2.1 μM) and a higher selectivity versus HO-1 rather than other heme-containing enzymes, including NOS [50]. On this basis, a new series of aryloxyalkyl derivatives of imidazole and 1,2,4-triazole (Table 2) was designed and synthesized. The compounds were tested on HO-1 and HO-2 isoforms isolated from the microsomal fractions of rat spleen and brain, respectively. In this series, it was evaluated how the type of azole moiety, the introduction of different substituents on the phenyl ring, and the modification of the length of the connecting oxyalkyl chain, can influence HO activity [55]. Concerning the effect of azole moiety, imidazole-based compounds generally resulted more potent than the corresponding triazole ones, as shown in Table 2 (compare compounds 8a and 8c vs 8b and 8d). Investigating the length of the alkyl chain, compounds with an oxybutyl linker gave better results than those containing an oxypropyl chain (compare compound 8c vs 8a). Finally, while an electron withdrawing moiety, such as 4-NO2, reduced activity, a halo-substituent, such as 4-I on the phenyl group gave good results for inhibition of HO-1, (Table 2, compounds 8e and 8f, respectively). Specifically, the presence of a 3-Br atom (compound 4) is the best substitution for inhibition of HO-1 but not for selectivity over HO-2; while a 4-I substituent (compound 8f) gave the best contribution in terms of potency and selectivity on HO-1.