Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

• Published in: Archiv der Pharmazie (Weinheim) Vol. 336; no. 11; pp. 523 - 540
• Main Authors: Kapková, Petra, Stiefl, Nikolaus, Sürig, Ulf, Engels, Bernd, Baumann, Knut, Holzgrabe, Ulrike
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.11.2003; WILEY‐VCH Verlag; Wiley; Wiley-VCH
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Binding Sites; Biological and medical sciences; Bispyridinium oxime ethers; Butyrylcholinesterase - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Inhibitors; Life Sciences & Biomedicine; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Pyridinium Compounds - chemical synthesis; Pyridinium Compounds - chemistry; Pyridinium Compounds - pharmacology; Science & Technology; Structure-Activity Relationship; CHOLINESTERASE; inhibitors; SITE; GALANTHAMINE; TORPEDO-CALIFORNICA; DESIGN; ALLOSTERIC MODULATORS; TACRINE; acetylcholinesterase; HUPERZINE-A; ANGSTROM RESOLUTION; POTENT; bispyridinium oxime ethers; Enzyme; Nitrogen heterocycle; Iminium compounds; Benzene derivatives; Enzyme inhibitor; Oxime; Esterases; Inhibitor enzyme complex; Acetylcholinesterase; In vitro; Modeling; Carboxylic ester hydrolases; Inhibitors; Structure activity relation; Bispyridinium oxime ethers; Six membered ring; Molecular model; Binding mode; Hydrolases; Aldoxime; Chemical synthesis; Organic dication
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200300795

A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB‐4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB‐4. Hence, the bisbenzyl ether of TMB‐4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so‐called DUO series), the lateral ring substitution was systematically varied. The lowest IC50 value against AChE found thus far in the DUO series was 0.34 μM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active‐site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.