Structure–Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles

Dolles, Dominik; Hoffmann, Matthias; Gunesch, Sandra; Marinelli, Oliviero; Møller, Jan; Santoni, Giorgio; Chatonnet, Arnaud; Lohse, Martin J.; Wittmann, Hans‐Joachim; Straßer, Andrea; Nabissi, Massimo; Maurice, Tangui; Decker, Michael

doi:10.1021/acs.jmedchem.7b01760

Cited by 58 publications

(93 citation statements)

References 74 publications

(139 reference statements)

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“…Results from further studies were in accordance with the role of BuChE in AD brains and showed a positive correlation between selective BuChE inhibition and improved cognitive performance and memory [9,10].…”

Section: Introductionsupporting

confidence: 74%

Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Askarani

Iraji

Rastegari

et al. 2020

Preprint

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To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities were evaluated including acetylcholinesterase (AChE), butylcholinesterase (BuChE), and Aβ1−42 aggregation inhibition as well as neuroprotective effects and metal-chelating properties. The results indicated highly selective BuChE inhibitory activity with IC50 values of 21.71 µM for compound 10 h as the most potent compound. Besides, compound 10 h could inhibit self-induced Aβ1−42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition value, respectively. A Lineweaver–Burk plot and molecular modeling study also showed that compound 10 h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10 h was potent as a selective Cu2+ chelator. Thus, the designed scaffold could be considered as multifunctional agents for AD drug discovery developments.

show abstract

Section: Introductionsupporting

confidence: 74%

Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Askarani

Iraji

Rastegari

et al. 2020

Preprint

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show abstract

“…A recent experiment with AChE knockout mice supported this hypothesis [ 9 ]. Results from further studies were in accordance with the role of BuChE in AD brains and showed a positive correlation between selective BuChE inhibition and improved cognitive performance and memory [ 10 , 11 ].…”

Section: Introductionsupporting

confidence: 63%

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

et al. 2020

View full text Add to dashboard Cite

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

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“…Besides that, it has been shown that BChE (over-)expression is associated with senile plaques and the transformation of non-fibrillar to fibrillary Aβ plaques. Hence, inhibition of BChE may be more therapeutically valuable than inhibition of AChE in later stages of AD and researches on selective BChE inhibitors are paid wide attention to in recent years 38 , 39 . In this study, the synthesized compounds to some degree showed inhibitory selectivity over BChE, although their potencies were not strong enough as nanomolar level, which at least gave a clue to search for new skeleton frame responsible for multifunctional PARP-1 and cholinesterase inhibition.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Gao

Wang

Cui

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.

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Structure–Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles

Cited by 58 publications

References 74 publications

Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

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