Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors:  Investigating Ligand−Peripheral Site Interactions

Abstract

Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino-1,2,3,4-tetrahydroacridine (tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to tacrine itself. AChE IC(50) values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC(50) values, suggesting the importance of ligand hydrophobicity for effective cation-pi interaction with the peripheral site.

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

“…The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography, CH 2 Cl 2 /MeOH/aqueous 30 % NH 3 (7:3:0.1 v/v), to afford products 9 a-f. Analytical data of the tacrine linkers 9 a-f are in good agreement with previously described data. [33] General procedure for the synthesis of TFAHs 10 a-n: A solution of the corresponding N 1 -(1,2,3,4-tetrahydroacridin-9-yl)alkane-1,ndiamine 9 a-e or N 1 -(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)alkane-1,8-diamine 9 f (1.0 mmol) and paraformaldehyde (1.0 mmol) in MeOH/CH 2 Cl 2 (7 mL, 3:1 v/v) was stirred for 1 h at room temperature. Ferulic acid (1.0 mmol) and the corresponding isocyanide (1.0 mmol) were then added, and the reaction was stirred for 24 h at room temperature.…”

“…9-Chlorotacrines 8 a,b were synthesized by following known procedures. [33][34][35] The latter chloro compounds were then treated with the appropriate alkylenediamines in 1-pentanol at reflux to obtain diamines 9 a-f. These diamines were then treated, by one-pot U-4CR, with formaldehyde, ferulic acid, and selected commercial isocyanides, in methanol/ dichloromethane (3:1 v/v) at room temperature for 24 h to obtain the expected TFAHs 10 a-n in 16-48 % overall yields (Scheme 1).…”

1,6-Bis[1-(2-chloro-5-thiazolylmethyl)-2-nitroiminoimidazolidin-3-yl]hexane and 1,3,5-tris[1-(6-chloronicotinyl)-2-nitroiminoimidazolidin-3-ylmethyl]benzene-Synthesis and insecticidal and neuroblocking activities in American cockroaches, Periplaneta americana

“…1) It is assumed that the primary role of the tether in a divalent drug is to reduce the loss of entropy that would occur upon binding two independent monomeric units. 1) The relationship between biological potency and the linker length has been discussed for bis-quaternary ammonium 2) and tacrine-based dimeric 3) acetylcholine esterase inhibitors, and many other divalent ligands. 1) We recently reported the first divalent neonicotinoid insecticides, alkylene-tethered bis-imidacloprid derivatives 4) and acyclic analogues.…”

Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles

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a b s t r a c tThe synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-aminopyridine-3,5-dicarbonitriles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range.

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