Pd-Catalyzed Direct Modification of an Anti-Alzheimer’s Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues

Wan, Lin-Xi; Miao, Shi-Xing; He, Zhenxiang; Li, Xiaohuan; Zhou, Xian‐Li; Gao, Feng

doi:10.1021/acsomega.1c03103

Cited by 10 publications

(5 citation statements)

References 23 publications

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“…18) The efficient olefin hydroamination developed by Baran and coworkers has not been used in any synthesis or modification of natural products until now. As part of our researches toward development of active molecules deriving from fascinating natural products, [19][20][21][22][23] this work applied the distinct and convenient method mentioned above to prepare 5α-arylamino-DHEAs which were further explored their potential anti-tumor activity. It is worth noting that when the reaction was used to structurally diversify the DHEA, only the 5α-substituted derivatives were produced, showing the good stereoselectivity (Chart 1).…”

Section: Chemical and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

Synthesis and Cytotoxicity Evaluation of Dehydroepiandrosterone Derivatives by Iron-Catalyzed Stereoselective Hydroamination

Wen

et al. 2023

Chem. Pharm. Bull.

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The direct modification of structurally complex natural product dehydroepiandrosterone (DHEA) through Iron-catalyzed direct hydroamination of DHEA with various nitro(hetero)arenes was carried out to afford 5α-arylamino-DHEAs (1-25) in good yields (53-72%). Though as a radical reaction, it features high stereoselectivity, and only the 5α-substituted derivatives were produced. The in vitro antiproliferative activity of these synthesized compounds against the human breast cancer MCF-7 cell was evaluated, showing that most of DHEA analogues possessed the moderate cytotoxic activity. The preliminary structure-activity relationship analysis revealed that the electron-withdrawing groups installed at the para-position of arylamine ring had a great contribution to the improvement of the DHEA's cytotoxic potency. Among them, (4-trifluoromethylaniline)-DHEA (4) displayed the most potent cytotoxicity, with an IC50 value of 19.3 μM, which was 2.3-fold more active than DHEA.

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Section: Chemical and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

Synthesis and Cytotoxicity Evaluation of Dehydroepiandrosterone Derivatives by Iron-Catalyzed Stereoselective Hydroamination

Wen

et al. 2023

Chem. Pharm. Bull.

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“…Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. Its clinical manifestations include loss of memory function, cognitive function, visual space function, and self-care ability. − The progression of AD is associated with loss of cholinergic transmission, oxidative damage, imbalance of metallics, excitotoxicity, and neuroinflammation, which can lead to a “domino” cascade of events in AD. − At this stage, the efficacy of most single drugs can only be based on delaying the course of the disease, and it is difficult to further prevent and block the course of the disease fundamentally and as a whole. Due to the complexity of AD disease, single-target drugs cannot provide an ideal therapeutic effect .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Activity of Donepezil: Aromatic Amine Hybrids as Anti-Alzheimerss Drugs

et al. 2023

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In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP–aniline hybrids (1–8), DNP–benzylamine hybrids (9–14), and DNP–phenylethylamine hybrids (15–21) were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound 3 exhibited excellent acetylcholinesterase inhibitory activity with an IC50 value of 4.4 μM, higher than that of positive control DNP and significant neuroprotective effects against H2O2-induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 μM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound 3 was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound 3 could be further explored as a lead compound for the treatment of Alzheimer’s disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents.

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“…For instance, fluorine-containing donepezil analogues fluoropezil possessing a longer drug-target residence time has been developed, which is preparing to enter phase II trial (Zhou et al, 2021;Qian et al, 2023). In our previous study, various nitrogen-containing functional groups were introduced into Unit C to provide a series of α-aryl donepezil analogues owning high AChE inhibition (Wan et al, 2021a). In order to find better anti-AD compounds, considering that the aromatic ring in Unit A is a vital binding site, we envisaged using aromatic nitrogen heterocycles in place of the phenyl group might form the additional bonding force to strengthen the AChE inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues

Xu,

Luo,

et al. 2023

Front. Chem.

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A series of novel N-aryl-debenzeyldonepezil derivatives (1–26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer’s disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer’s disease.

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Pd-Catalyzed Direct Modification of an Anti-Alzheimer’s Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues

Cited by 10 publications

References 23 publications

Synthesis and Cytotoxicity Evaluation of Dehydroepiandrosterone Derivatives by Iron-Catalyzed Stereoselective Hydroamination

Synthesis and Cytotoxicity Evaluation of Dehydroepiandrosterone Derivatives by Iron-Catalyzed Stereoselective Hydroamination

Design, Synthesis, and Biological Activity of Donepezil: Aromatic Amine Hybrids as Anti-Alzheimerss Drugs

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues

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