4-tert-Pentylphenoxyalkyl derivatives – Histamine H3 receptor ligands and monoamine oxidase B inhibitors

Dual Target Ligands with 4-tert-Butylphenoxy Scaffold as Histamine H3 Receptor Antagonists and Monoamine Oxidase B Inhibitors

“…The highest activity was observed for the compounds with the propylene linker (DL76, 9, 12, 16, 20, 24, and 28). This observation is simillar to our previous finding [12] concerning 4-tert-amylphenoxy derivatives as DTL ligands. Exchange of a cyclic amine group (piperidine in DL76) for other moieties (pyrrolidine, substituted piperidine, or azepane) caused variable influences: increased (pyrrolidine-5 or 2-methylpiperidine-9), maintained (azepane-28), or decreased activity (3-methylpiperidine-12, 3,3-dimethylpiperidine-16, 3,5-dimethylpiepridine-20, or 4-methylpiperidine-24).…”

“…Moreover, Affini et al [11] described indanone derivatives as DTL for PD (compound 2; hH 3 R K i = 6.5 nM; hMAO B IC 50 = 276 nM; Figure 2). Recently, we have described a new group of DTL hMAO B inhibitors, tert-amylphenoxy derivatives [12]. These compounds showed also affinity for hH 3 R (e.g., compound 3; Figure 2).…”

“…The compounds showed variable affinities for hH 3 R ranging from good (K i < 100 nM) to weak (K i > 1500 nM), depending on the kind of the introduced cyclic amine moiety and alkyl chain length. Analyzing the influence of a cyclic amine moiety on the affinity for hH 3 R, it was noticed that derivatives of piperidine (DL76, 6-8), 3-methylpiperidine (12)(13)(14)(15), and azepane (28)(29)(30)(31) were the most active. On the other hand, 3,3-dimethylpiperidine derivatives (16)(17)(18)(19) showed weaker affinities (K i > 1600 nM).…”

“…To investigate the type of inhibition (reversible or irreversible) of hMAO B by 4-tert-butylphenoxy derivatives, experiments were performed with selected compounds (DL76, 5, and 9) and conducted as described previously [12]. Rasagiline (irreversible inhibitor) and safinamide (reversible inhibitor) were used as standards.…”

“…4-tert-Butylphenoxyalkyl bromides (4a-4d) were synthesized according to the method described previously [14]. All of them are known and reported in Chemical Abstract Database: Designed compounds 5-31 were synthesized according to the procedure described previously [12]. Briefly, to a proper 4-tert-butylphenylalkoxy bromide (2.5 mmol) in the mixture of C 2 H 5 OH (52.5 mL) and H 2 O (10 mL) and in the presence of K 2 CO 3 (7.5 mmol) with the catalytic amount of KI was added a proper amine (5 mmol), and the solution was refluxed from 10 to 48 h. Then, C 2 H 5 OH was evaporated, and to the residue were added 50 mL of CH 2 Cl 2 and 40 mL of water.…”