Synthesis, Biological Evaluation and Molecular Docking Study of Hydrazone-Containing Pyridinium Salts as Cholinesterase Inhibitors

Abstract

A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman's colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Key words acetylcholinesterase inhibitor; butyrylcholinesterase inhibitor; docking study; pyridinium salt; hydrazone Acetylcholinesterase (AChE) is an enzyme which is responsible for the hydrolysis of acetylcholine (ACh).1) AChE inhibitors bind to the enzyme thereby increases the level of acetylcholine by inhibiting the hydrolysis of ACh to choline and acetate.2) AChE inhibitors are used as therapeutic agents in the treatment of disorders related to ACh diminution such as Alzheimer disease, myasthenia gravis, glaucoma.3) AChE has a deep, narrow gorge approximately 20 Å long. Catalytic active site (CAS) of the enzyme is located at the bottom of the gorge whereas peripheral anionic site (PAS) is at the entrance. 4) Although anti-AChE drugs show a wide range of chemical diversity, they generally include aromatic-heterocyclic ring systems and a nitrogen atom as chemical structure (Fig. 1). These structures have an important role for the interaction with specific amino acids in the enzyme.5) Aromaticheterocyclic nuclei generally have potential hydrophobic and charge-transfer interaction, while nitrogen atom and its quaternary form can make hydrogen or ionic bonds as well as dipole-dipole or ion-dipole interactions with amino acids in the enzyme gorge.5-10) In addition, quaternary nitrogen cation displays highly positive binding stabilization due to cation-π interactions with amino acid residues in AChE enzyme. [9][10][11][12] Many reports indicated that compounds bearing aromatic/ heteroaromatic rings on lateral parts of pyridinium displayed high AChE inhibitory activity and act as dual binding inhibitors. [13][14][15][16] According to the docking studies of these compounds, it was found that both terminal rings attached to the pyridinium were able to bind simultaneously to both CAS and PAS of the enzyme resulting in higher AChE inhibitory activity. [13][14][15][16] Among the reported studies, pyridinium derivatives having benzofuran ring were shown to have a significant AChE inhibitory activity and it was observed that benzofuran and phenyl moieties as terminal rings were interacted with both PAS and CAS of AChE. 15,16) On the other hand, many of compounds bearing hydrazonehydrazide functional group have been reported to possess ChE inhibitory activity. 17,18) The hydrazones have hydrogen donor and acceptor nitrogen atoms an...

Computational Evaluation and Anti-inflammatory and Analgesic Activities of Nebrodenside A Isolated From Dodonaea viscosa

“…Initially, energy minimization of the enzyme was done utilizing the AMBER99 force field before molecular docking. Nebrodenside A was then constructed and the missing H-atoms were added using the protonate 3D module and its structure was energy minimized using the MMFF94 force field presented in Parlar et al 15 and Soyer et al 16…”

7-Substituted pyrrolo[2,3-d]pyrimidines for the synthesis of new 1-deazapyrimido[1,2,3-cd]purines

“…To synthesize the 2-unsubstitutеd 1- imidazolium, pyridinium or isoquinolinium rings have been described as inhibitors of acetylcholinesterase (AChE) [25,26]. AChE catalyzes the hydrolysis of acetylcholine and plays a key role in the termination of the transmission of nerve impulses.…”

Synthesis of new imidazole-hydrazone derivatives and anticholinesterase activity

“…Hidrazon fonksiyonel grubu taşıyan inhibitör aktivitesine sahip bileşiklerin çoğu, çeşitli çalışmalarda bildirilmiştir. Hidrojen donörüne sahip olan hidrazonlar ve alıcı azot atomları, enzimin aktif yöresindeki amino asitlerle hidrojen bağları oluşturabilirler [14,15].…”

“…Hidrazon fonksiyonel grubu taşıyan inhibitör aktivitesine sahip bileşiklerin çoğu, çeşitli çalışmalarda bildirilmiştir. Hidrojen donörüne sahip olan hidrazonlar ve alıcı azot atomları, enzimin aktif yöresindeki amino asitlerle hidrojen bağları oluşturabilirler [14,15]. Bu çalışmada imidazol ve hidrazon yapısı taşıyan yeni N'-((1H-imidazol-2yl)methylen)substitute benzohidrazit türevi bileşikler sentezlenmiş ve AChE inhibisyon potansiyelleri değerlendirilmiştir.…”