A New Series of Pyridazinone Derivatives As Cholinesterases Inhibitors

Pharmacological Reports 71 (2019) 1253–1263 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies a, b c d a,e Azime Berna Özçelik *, Zeynep Özdemir , Suat Sari , Semra Utku , Mehtap Uysal a Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey b _ Inönü University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Malatya, Turkey c Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey d Mersin University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Mersin, Turkey e Erzincan Binali Yıldırım University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Erzincan, Turkey A R T I C L E I N F O A B S T R A C T Article history: Background: The pyridazinone nucleus has been incorporated into a wide variety of therapeutically Received 17 April 2019 interesting molecules to transform them into better drugs. Acetylcholinesterase (AChE) and Received in revised form 8 July 2019 butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis Accepted 19 July 2019 of acetylcholine (ACh). Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease. Available online 22 July 2019 Here, we prepared 12 new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives and evaluated their inhibitory effects on AChE/BChE in pursuit of Keywords: potent dual inhibitors for Alzheirmer’s Disease. We also tried to get insights into binding interactions of AChE inhibitor the synthesized compounds in the active site of both enzymes by using molecular docking approach. BChE inhibitor 3(2H)-Pyridazinone Method: We obtained our compounds by the reaction of various substituted/nonsubstituted Hydrazone benzenesulfonic acid derivatives with 6-substitutedphenyl-3(2H)-pyridazinone-2-yl acetohydrazide ’ Molecular modelling and determined their anticholinesterase activities according to the Ellman s method. Molecular docking studies were done using Glide and the results were evaluated on Maestro (Schrödinger, LLC, New York, NY, 2019). Results: The title compounds showed moderate inhibition at 100 mg/ml against both enzymes, yet with better activity against BChE. Compound VI2a emerged as a dual inhibitor with 25.02% and 51.70% inhibition against AChE and BChE, respectively. Conclusion: This study supports that novel pyridazinone derivates may be used for the development of new BChE inhibitory agents. It was less potent than the reference drugs, yet promising for further modifications as a lead. The ability of the compounds to adopt energetically more favourable conformations and to engage in more key interactions in the ECBChE active gorge explains their better activity profile against ECBChE. © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. Introduction compound space due to the coordination capability of nitrogen [2]. Recent studies have found that pyridazine is one of the most Pyridazines are six-membered dinitrogen heterocycles often developable heteroaromatic rings for new drugs with eligibility to found in three different isomers, namely pyridazine (1,2-diazine), formligandstowardsdifferenttargets,itisalso found inthestructure pyrimidine (1,3-diazine) and pyrazine (1,4-diazine) [1]. Nitrogen- of natural compounds displaying various biological activities. containing heteroaromatic rings make up part of the bioactive Applications of substituted pyridazines as antidepressant, anti- hypertensive, anticonvulsant, antibacterial, diuretic, anti-HIV, anticancer, anti-inflammatory, analgesic, cardiovascular, and neuro- protective agents are available in the literature [3–13]. Some Abbreviations: AChE, acethylcholine esterase; AD, Alzheimer’s disease; BChE, examples for medical use of pyridazine derivatives are zardaverine buthyrylcholine esterase; CBS, cation-binding pocket; PAS, peripheral anionic site; and imazodane as cardiotonic PDE III inhibitors and emorfazone as SEM, standard error mean. an analgesic agent (Fig. 1) [6–8]. Xing et al. synthesized 2,6- * Corresponding author. E-mail address: [email protected] (A.B. Özçelik). disubstituted pyridazinone analogs and investigated their http://dx.doi.org/10.1016/j.pharep.2019.07.006 1734-1140/© 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. 1254 A.B. Özçelik et al. / Pharmacological Reports 71 (2019) 1253–1263 Fig. 1. Structure of the drugs bearing pyridazinone skeleton and compound 4 [14]. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in- long time. But only ensaculin, a coumarin derivative composed of hibitor activities. Among them, compound 4 was reported to be benzopyran and a piperazine substituted moiety, has appeared to highly potent and selective against the cited enzymes (Fig. 1) [14]. prevent or slow down the progressive neurodegeneration [22–25]. Alzheimer disease (AD) is well-known for over a century, Ensaculin has been used clinically for the treatment of AD as an however, there is no concrete therapeutic treatment prevailed [15– AChEI for a long time. 17]. There is relationship between AD and changes in many Although BChE is sparsely expressed in humans, recent studies neurotransmitters, including cholinergic, noncholinergic, seroto- proved that AChE inhibition alone may not be sufficient to reduce nergic, dopaminergic, aminoacidergic, and neuropeptidergic; but cholinesterase activity and choline levels may elevate since BChE the relationship between changes in the cholinergic system and AD makes up for the lost AChE activity. Furthermore, it is known that is the most well-known. According to this relationship described as BChE expression is increased during AD [26,27]. Several studies, so cholinergic hypothesis, decrease in acetylcholine and choline far, have emphasized the importance of dual ChE inhibition in AD acetyl transferase levels is associated with AD [18]. Post-mortem and other neurological disorders with cognitive decline. Drugs brain studies and altered cholinergic symptoms such as degenera- such as rivastigmin are efficacious in AD thanks to their dual- tion of neurons controlling neocortical regions, loss of cholinergic inhibitory character [28]. terminals in the cerebral cortex, loss of choline acetyl transferase Zhou et al. designed and synthesized three different groups of activity and acetyl choline synthesis, decreased cholinergic coumarin-like compounds (A, B, C) bearing phenylpiperazine rings receptivity and increased AChE activity, which can be seen in as substitution to evaluate their potential for treating AD (Fig. 3) many Alzheimer's patients [19,20]. For this reason, in the [25]. Zhou et al. also reported three hypothesis for the AChEI treatment of AD increasing acetylcholine level by suppressing activity of their derivatives: (1) the coumarin ring, 2-(H)-chromen- AChE enzyme is one of the frequently used treatment modalities. 2-one, a heterocyclic moiety involved in ensaculin’s structure are On this basis, AChE inhibitors (AChEIs) have become the leading responsible for cognitive functions and compatible with high anti- strategy for the development of anti-AD agents. The current AChE potency, interacting with the peripheral anionic site (PAS); interest in these drugs has received considerable attention, too (2) the nitrogen atom from the phenylpiperazine group acting as [21–23]. Some AChEIs, such as tacrine, donepezil, rivastigmine, and the positive charge center presented in many potent AChE ensaculin (Fig. 2), show modest improvement in memory and inhibitors, which can interact with the catalytic center of AChE cognitive functions, and have been used to treat AD clinically for a demonstrated by the X-ray crystallographic studies of the AChE- Fig. 2. Structure of some FDA-approved AChEI in AD. A.B. Özçelik et al. / Pharmacological Reports 71 (2019) 1253–1263 1255 Fig. 3. Structural hypothesis for AChEIs and some designed compounds from the literature [25]. donepezil and AChE-galantamine complexes, and (3) the phenyl In view of the above mentioned findings, we designed and ring is connected with the piperazine ring interacting with the synthesized the title compounds (VI1a-1d, VI2a-2d, VI3a-3d) to cation-binding pocket (CBS) as shown in Fig. 3 [25]. In addition, a provide the structural requirements for AChEI and BChEI activities linker chain bearing different numbers of carbon atom at the (Fig. 4). We in vitro evaluated their AChE and BChE inhibitory second position of the pyridazinone ringmight interact with the effects using Ellman’s method, the most commonly used method residues lining the wall of the AChE gorge. to measure cholinesterase activity [29]. Fig. 4. Structural hypothesis for the title compounds [25]. 1256 A.B. Özçelik et al. / Pharmacological Reports 71 (2019) 1253–1263 The CBS moiety was designed as substituted phenyl ring and the converted to the free base form with ammonium hydroxide. The structural modifications were focused on substitutions on the precipitate was collected by filtration, washed with water until phenyl rings expected to interact with the CBS and PBS. Methoxy, neutral, dried, and crystallized from ethanol-water [38]. chloro, bromo, and fluoro groups were included as substitutions

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