Ionic liquid-enabled synthesis,cholinesterase inhibitory activity,and molecular docking study of highly functionalized tetrasubstituted pyrrolidines

A small library of novel spiropyrrolidine heterocyclic hybrids has been prepared regioselectively in 1-butyl-3-methylimidazoliumbromide ([bmim]Br) with good to excellent yields using a [3+2] cycloaddition reaction. These synthesized compounds were evaluated as potential agents for treating Alzheimer’s disease. Compound 4b showed the most potent activity, with an IC₅₀ of 7.9 ± 0.25 µM against acetylcholinesterase (AChE). The inhibition mechanisms for the most active compounds on AChE and butyrylcholinesterase (BChE) receptors were elucidated using molecular docking simulations.     

Design,synthesis and cholinesterase inhibitory activity of novel spiropyrrolidine tethered imidazole heterocyclic hybrids

A small library of structurally fascinating spiropyrrolidine tethered imidazole heterocylic hybrids has been synthesized regioselectively in good yields employing [bmim]Br mediated 1,3-diplar cycloaddition strategy. The new class of azomethine ylide generated in situ from l-histidine and 11H-indeno[1,2-b]quinoxalin-11-one reacts with various substituted β-nitrostyrenes affording the spiropyrrolidine tethered imidazole heterocylic hybrids. Compounds thus synthesized were assessed for their in vitro cholinesterase (ChEs) inhibitory activities, among them compounds possessing 4-methyl and 4-methoxy substituents on the aryl ring showed potent activities with IC₅₀ values of 2.02 ± 0.05 and 2.05 ± 0.06 μM against AChE and 12.40 ± 0.14 and 11.45 ± 0.28 μM against BChE enzyme, respectively. In addition, the most active compounds were performed for their molecular docking simulation and the results revealed interesting binding templates to the active site channel of cholinesterase enzymes.     

Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC₅₀ values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC₅₀ values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC₅₀ values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.     

Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors

A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer’s disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC₅₀ values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs.     

Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis,cholinesterase inhibitory activity and their molecular docking simulation

A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-b]quinoxaline heterocyclic hybrids 7a–j were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomethine ylide employed is first of its kind and generated in situ from indenoquinoxalinone and l-tryptophan, a combination that has not been employed previously for the in situ generation of azomethine ylides. The synthesized heterocyclic hybrids 7a–j were evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 7h and 7j displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC₅₀ values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.     

Design,synthesis, biological evaluation,and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC₅₀ to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer’s disease (AD) treatment.     

Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC₅₀ values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC₅₀ = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC₅₀ for AChE = 0.16 µM and IC₅₀ for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC₅₀ for AChE = 0.59 µM and IC₅₀ for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.     

Cholinesterase inhibitory activity versus aromatic core multiplicity: A facile green synthesis and molecular docking study of novel piperidone embedded thiazolopyrimidines

Novel thiazolopyrimidine derivatives have been synthesized via microwave assisted, domino cascade methodology in ionic liquid and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Among the newly synthesized compounds 6d, 6a, 6e and 6b displayed higher AChE inhibitory activity than standard drug, galanthamine, with IC₅₀ values of 0.53, 1.47, 1.62 and 2.05 μM, respectively. Interestingly, all the compounds except for 6m–r and 6x displayed higher BChE inhibitory potentials than galanthamine with IC₅₀ values ranging from 1.09 to 18.56 μM. Molecular docking simulations for 6d possessing the most potent AChE and BChE inhibitory activities, disclosed its binding interactions at the active site gorge of AChE and BChE enzymes.     

Synthesis and cholinesterase inhibitory activity study of new piperidone grafted spiropyrrolidines

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, which affected 35 million people in the world. The most practiced approach to improve the life expectancy of AD patients is to increase acetylcholine neurotransmitter level at cholinergic synapses by inhibition of cholinesterase enzymes. A series of unreported piperidone grafted spiropyrrolidines 8(a-p) were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Therein, compounds 8h and 8l displayed more potent AChE enzyme inhibition than standard drug with IC₅₀ values of 1.88 and 1.37 µM, respectively. Molecular docking simulations for 8l possessing the most potent AChE inhibitory activities, disclosed its interesting binding templates to the active site channel of AChE enzymes. These compounds are remarkable AChE inhibitors and have potential as AD drugs.     

Microwave assisted synthesis,cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives

A series of hitherto unreported pyrido-pyrimidine-2-ones/pyrimidine-2-thiones were synthesized under microwave assisted solvent free reaction conditions in excellent yields and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Among the pyridopyrimidine derivatives, 7e and 7l displayed 2.5- and 1.5-fold higher enzyme inhibitory activities against AChE as compared to standard drug, galanthamine, with IC₅₀ of 0.80 and 1.37 μM, respectively. Interestingly, all the compounds except 6k, 7j and 7k displayed higher inhibitory potential against BChE enzyme in comparison to standard with IC₅₀ ranging from 1.18 to 18.90 μM. Molecular modeling simulations of 7e and 7l was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) and human butyrylcholinesterase (hBChE) enzymes to disclose binding interaction and orientation of these molecule into the active site gorge of respective receptors.     

Synthesis and cholinesterase inhibitory activity of new 2-benzofuran carboxamide-benzylpyridinum salts

A series of benzofuran-2-carboxamide-N-benzyl pyridinium halide derivatives (6a-o) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N-((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N-((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds (6a-o). The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC₅₀ values in the range of 0.054–2.7 µM. In addition, good inhibitory effects on Aβ self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 µM, respectively).     

Preparation,anticholinesterase activity and molecular docking of new lupane derivatives

A set of twenty one lupane derivatives (2–22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure–activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC₅₀ value of 21.5 μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme.     

3,4-Dihydroquinazoline derivatives inhibit the activities of cholinesterase enzymes

A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound 8b and 8d were the most active compounds in the series against BChE with IC₅₀ values of 45 nM and 62 nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound 8b and 8d bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.     

Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies

One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1:1:1 and 1:2:2 furnished to mono- and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 2.36–9.43 μM. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC₅₀ values of lower than 10 μM displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC₅₀ values of 7.44–19.12 μM. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC₅₀ values of 2.35 and 3.21 μM, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated K_i values of 2.01 and 6.76 μM, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC₅₀ values and free binding energy values of the synthesized compounds docked into the active site of the enzymes.     

Molecular docking and molecular dynamics simulation approaches for identifying new lead compounds as potential AChE inhibitors

To provide hints for the design of novel acetylcholinesterase (AChE) inhibitors with higher potency and specificity, the binding modes of the (RS, S)-17b and (RS, R)-17b enantiomers on AChE were chosen to investigate by molecular docking and molecular dynamics simulation. The results show that the binding modes of (RS, S)-17b and (RS, R)-17b are clearly different from each other. In particular, the (RS, S)-17b and (RS, R)-17b enantiomers tend to be planar and bend conformations to interact with AChE, respectively. Furthermore, based on the binding mode on AChE and structure modification of (RS, S)-17b, two novel inhibitors (1 and 2) with higher inhibitory activity were designed. Our design strategy suggests that the number of N and O atoms should be increased, the 5, 6-dimethoxy should be transformed into ring and the indanone moiety should be ring-opening, which would result in generating potent and selective AChE inhibitors.     

Design,synthesis and biological evaluation of benzofuran appended benzothiazepine derivatives as inhibitors of butyrylcholinesterase and antimicrobial agents

A series of bezofuran appended 1,5-benzothiazepine compounds 7a–v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC₅₀ value ranging between 1.0?±?0.01 and 72?±?2.8?μM when compared with the standard donepezil (IC₅₀, 2.63?±?0.28?μM). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC₅₀ values of 1.0, 1.0 and 1.8?μM, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.     

Design,synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors

A series of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized, Furthermore, their inhibitory activities against acetylcholinesterase in vitro were tested by Ellman spectrophotometry, and the results of inhibitory activity test showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro. Moreover, the IC₅₀ value of compound 4f was to 0.66 μM, which was higher than that of Rivastigmine and Huperzine-A as reference compounds, and it had a weak inhibitory effect on butyrylcholinesterase. The potential binding mode of compound 4f with AChE was investigated by the molecular docking, and the results showed that 4f was strongly bound up with AChE with the optimal conformation, in addition, their binding energy reached −11.27 Kcal*mol⁻¹. At last, in silico molecular property of the synthesized compounds were predicted by using Molinspiration online servers. It can be concluded that the lead AChEIs compound 4f presented satisfactory drug-like characteristics.     

New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation

A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer’s disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC₅₀ = 0.059 μΜ) with mixed type inhibition scenario. Structure-activity relationship revealed that three-carbon alkyl chain connecting coumarin and triazole is well tolerable for inhibitory potential. Hybrids obtained from 4-hydroxycoumarin and 1-benzotriazole were most potent AChE inhibitors. The inhibitory potential of all compounds against butyrylcholinesterase was also evaluated but all showed negligible activity suggesting that the hybrid molecules are selective AChE inhibitors. 13b (most potent AChE inhibitor) also showed copper-induced Aβ_1-42 aggregation inhibition (34.26% at 50 μΜ) and chelating properties for metal ions (Cu²⁺, Fe^2+, and Zn²⁺) involved in AD pathogenesis along with DNA protective potential against degenerative actions of OH radicals. Molecular modelling studies confirm the potential of 13b in blocking both PAS and CAS of AChE. In addition, interactions of 13b with Aβ_1-42 monomer are also streamlined. Therefore, hybrid 13b can act as an effective hit lead molecule for further development of selective AChE inhibitors as multifunctional anti-Alzheimer’s agents.     

A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC₅₀ values ranging from 0.044 to 5.80?µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC₅₀ values of 0.058 and 0.044?µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC₅₀ values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.     

Design,synthesis and evaluation of pyrazolopyrimidinone derivatives as novel PDE9A inhibitors for treatment of Alzheimer’s disease

Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer’s disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC₅₀ of 2.0 nM against PDE9, showed good metabolic stability (t_1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification.