Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies

Sang, Zhipei; Bai, Ping; Ban, Yujuan; Wang, Keren; Wu, Anguo; Mi, Jing; Hu, Jiaqi; Xu, Rui; Zhu, Guoqi; Wang, Jianta; Zhang, Jiquan; Wang, Changning; Tan, Zhenghuai; Tang, Lei

doi:10.1016/j.bioorg.2022.106007

Cited by 12 publications

(9 citation statements)

References 37 publications

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“…The possible interacting mechanism of compound 3f with hAChE (PDB code: 4ey4) and hBuChE (PDB code: 4tpk) was carried out using AUTODOCK 4.2 package, respectively 22 , 23 . It had been reported that amino acid residues Tyr72, Asp74, Trp86, Tyr124, Trp286, Tyr337, Phe295 and Phe297 were the key active site residues of hAChE 30 .…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, rivastigmine is a dual AChE/BuChE inhibitor approved by FDA for the treatment of mild to moderate AD 21 . The carbamate moiety is the pharmacophore, and many carbamate derivatives have been developed as multifunctional agents anti-AD by our group and other groups 22–25 . Herein, we plan to introduce carbamate moiety into the promising quinoline skeleton to obtain novel quinoline-rivastigmine hybrids by MTDLs ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Chen

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of novel quinoline- O -carbamate derivatives was rationally designed for treating Alzheimer’s disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual ee AChE/eqBuChE inhibitor with IC 50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound 3f presented significant neuroprotective effect on A β 25-35 -induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl 3 -induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Chen

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Moreover, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors have shown remarkable roles in the preservation of cholinergic functions and symptomatic improvement in AD [ 13 , 14 ]. In view of MTDLs merits, the contemporary medicinal chemists have focused their efforts, over the past few decades, to develop new chemical entities as multiple-acting MAO-B and AChE/BChE inhibitors [ 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Further, chalcone, 1,3-diphenylprop-2-en-1-one, represents a substantial flexible scaffold for the design of selective MAO-B and/or AChE inhibitors [ 25 ], where the existence of propenone (α-β unsaturated ketone) and three rotatable bonds in chalcones can furnish various binding orientations with multiple targets [ 26 ]. Recent studies pointed out that conjugation of certain FDA-approved drugs, such as rivastigmine and donepezil, with chalcone scaffold led to generation of multifunctional MAO-B/ChE inhibitors, such as compound I with potent neuroprotective properties for AD [ 15 ]. Installing different electron-pulling and pushing groups on the aryl/heteroaryl rings of chalcones can modulate the electrophilic character of the Michael acceptor propanone as exemplified by chalcones II and III [ 27 , 28 ], where the introduction of lipophilic halogens (F, Cl, Br)/electron donation groups (-OMe, -N(Me) 2 ) onto the phenyl B ring of chalcones afford highly selective MAO-B inhibitors such as compound IV [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

et al. 2023

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Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.

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“…[17] flavonoids, and isoflavonoids. [18] Chalcones and their derivatives (Figure 2) are associated with an abundance of biological actions such as anticancer , [19] anti-Alzheimer, [20] antiinflammatory, [21] anticonvulsant, [22] anti-allergic, [23] antimicrobial, [24] anti-malarial, [25] anti-ulcerative, [26] antileishmanial, [27] and anti-spasmodic. [28] Lately, a novel series of pyrazolyl-chalcone analogs synthesized by M.G.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Antimicrobial Screening and Docking Studies of Newer 1,4‐Dihydropyridine tethered Chalcone Hybrids

Kumar¹,

Kumar

Upadhyay³

et al. 2022

ChemistrySelect

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The evolution of antimicrobial drug resistance demands the development of more effective therapeutics that are more potent with reduced side effects. In the present study, we reported the design and synthesis of 1,4-dihydropyridine clubbed with chalcone hybrids in excellent yields. Further, the biological assessment of these 1-phenyl-3-dihydropyridineprop-2-en-one chalcone hybrids as antimicrobial agents was accomplished against strains E.coli, Klebsiella pneumonia, Salmonella typhi, Staphylococcus aureus, Candida albicans (Yeast), Aspergillus niger, Alternaria solani and Fusarium oxy-sporum by well diffusion method in terms of zone of inhibition (in mm). Some Hybrids displayed the best anti-microbial activity against all the tested strains. A molecular docking study was performed for the most active compounds and showed the best binding pose with the highest binding score within the active sites of S. aureus DNA gyrase complexed with DNA and Lanosterol 14α-demethylase. These novel products evolved as promising leads for the future development of more potent anti-microbial compounds.

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Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies

Cited by 12 publications

References 37 publications

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

Design, Synthesis, Antimicrobial Screening and Docking Studies of Newer 1,4‐Dihydropyridine tethered Chalcone Hybrids

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