JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2023
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IF 5.6
Changjun Zhang,Yujia Zhang,Yangjing Lv,Jianan Guo,Bianbian Gao,Yi Lu,Anjie Zang,Xi Zhu,Tao Zhou,Yuanyuan Xie
Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation.
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Frontiers in Pharmacology
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2022
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IF 5.988
Wang Yue,Wu Xinyan,Yang Kailin,Liu Qing,Jiang Baoping,Yang Runmei,Xiao Peigen,He Chunnian
Paeonia suffruticosa (Moutan) is a traditional medicinal plant in China. Its seed coat is rich in resveratrol oligomer, especially suffruticosol B (SB). Previous studies had shown that the seed coat extracts of Paeonia suffruticosa (PSCE) had good cholinesterase inhibitory activity and neuroprotective effect, but the effective dose range was unknown, and the pharmacodynamic components and molecular mechanism of PSCE had not been discussed. The current study aimed to screen the pharmacodynamic components in PSCE and investigate the improvement effect of PSCE and the selected SB on scopolamine-induced cognitive dysfunction in mice and its mechanism. The results of high-throughput sequencing and bioinformatics analysis showed that suffruticosol B (SB) and trans-gnetin H (GH) might be the main active components of PSCE; PSCE might improve cognitive dysfunction through p53, HIF-1, MAPK, and PI3K-Akt signaling pathways, while SB and GH might improve cognitive dysfunction through HIF-1 signaling pathway. SB and GH had good molecular docking activity with the target of HIF-1 signaling pathway. The pharmacodynamic activities of PSCE and SB were further verified by behavioral experiments. PSCE and SB could improve the recognition ability of familiar and new objects and shorten the escape latency in the Morris Water Maze test (PSCE 120 mg∙kg-1, p < 0.05; SB 60 mg∙kg-1, p < 0.01); PSCE and SB could increase Ach and GSH levels, enhance the activities of ChAT, SOD and CAT, decrease the levels of IL-1β, IL-6, and TNF-α, and decrease the activity of AChE. In conclusion, the results indicated that PSCE might exert pharmacodynamic activity through multiple components, targets, and pathways, and SB and GH might be the main active components of PSCE. PSCE and SB might improve cognitive dysfunction by regulating cholinergic, antioxidant, and anti-inflammatory effects. These results indicated that PSCE and SB might be potential anti-AD drug candidates, providing a scientific basis for the development and utilization of Moutan bark.
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Food Bioscience
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2022
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IF 5.318
Jingru Zheng,Yuanhong Gao,Jie Ding,Na Sun,Songyi Lin
The study aims to investigate the repair effects of Ser-Ser-Asp-Ala-Phe-Phe-Pro-Phe-Arg (SSDAFFPFR) and Ser-Asn-Val-Phe-Asp-Met-Phe (SNVFDMF) peptides on scopolamine-caused memory impairment in mice. Behavioral experiments have revealed that Antarctic krill peptides can ameliorate scopolamine caused memory impairment by changing the behavior of mice. In comparison with the scopolamine group, the two peptides at a dose of 40 mg/kg could improve memory impairment. The serum SOD activity (82.82 ± 0.19 vs 79.47 ± 2.42 U/mg prot) and hippocampal ACh level (101.46 ± 3.23 vs 99.85 ± 7.13 μg/mg prot) of SSDAFFPFR were higher than those of SNVFDMF. Hippocampal AChE activity (0.20 ± 0.03 vs 0.53 ± 0.02 U/mg prot), hippocampal MDA level (1.56 ± 0.01 vs 1.63 ± 0.05 nmol/mg prot) and the serum MDA level (3.38 ± 0.24 vs 3.88 ± 0.21 nmol/mg prot) was lower than that of SNVFDMF. The state of mouse hippocampal cells was further observed by a microscopic imaging system. In addition, western blot analysis showed that SSDAFFPFR could significantly inhibit the expression of Bax, caspase-3, and p53, and promote the expression of BCL-XL, CREB, and BDNF, thus protecting hippocampal neurons in mice. In conclusion, the Antarctic krill peptide can repair scopolamine-induced memory impairment in mice.
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BIOORGANIC CHEMISTRY
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2022
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IF 5.307
Chuansheng Yao,Xiaoying Jiang,Rui Zhao,Zhichao Zhong,Jiamin Ge,Junlong Zhu,Xiang-Yang Ye,Yuanyuan Xie,Zhen Liu,Tian Xie,Renren Bai
A series of N -propargylamine-hydroxamic acid/ o -aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer’s disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC 50 = 99.0 nM; HDAC1, IC 50 = 21.4 nM) and excellent MAO selectively (MAO-A, IC 50 = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aβ1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer’s disease.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
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IF 5.895
Yue Zhao,Zhiqiang Lu,Xiaomeng Xu,Na Sun,Songyi Lin
The incidence of neurodegenerative diseases related to cognitive decline and memory loss is on the rise as the global elderly population increases. In this study, we evaluated the effect of the sea cucumber-derived peptide Phe–Tyr–Asp–Trp–Pro–Lys (FYDWPK) on scopolamine-induced neurotoxicity in an animal model. The Morris water maze, passive avoidance apparatus, and shuttle box test were used to assess learning and memory abilities. In behavioral tests, FYDWPK effectively alleviated learning and memory impairment. FYDWPK also alleviated cholinergic dysfunction in mice with dementia. Furthermore, FYDWPK significantly improved oxidative imbalance by increasing superoxide dismutase activity and decreasing malondialdehyde levels (P < 0.05). The pathological results showed that FYDWPK alleviated neuronal loss, blurred caryotheca, and pyknotic nuclei in the hippocampus, and a high dose of FYDWPK had the best effect. In conclusion, FYDWPK alleviated cognitive and memory impairments by regulating oxidative imbalance, reducing cholinergic dysfunction, and relieving pathological alterations.
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BRITISH JOURNAL OF PHARMACOLOGY
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2023
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IF 7.3
Leilei Pan,Shuifeng Xiao,Zichao Xu,Wenping Li,Long Zhao,Ling Zhang,Ruirui Qi,Junqin Wang,Yiling Cai
Background and Purpose We evaluated the hypothesis that central orexin application could counteract motion sickness responses through regulating neural activity in target brain areas. Experimental Approach Thec effects of intracerebroventricular (i.c.v.) injection of orexin-A and SB-334867 (OX 1 antagonist) on motion sickness-induced anorexia, nausea-like behaviour (conditioned gaping), hypoactivity and hypothermia were investigated in rats subjected to Ferris wheel-like rotation. Orexin-A responsive brain areas were identified using Fos immunolabelling and were verified via motion sickness responses after intranucleus injection of orexin-A, SB-334867 and TCS-OX2-29 (OX 2 antagonist). The efficacy of intranasal application of orexin-A versus scopolamine on motion sickness symptoms in cats was also investigated. Key Results Orexin-A (i.c.v.) dose-dependently attenuated motion sickness-related behavioural responses and hypothermia. Fos expression was inhibited in the ventral part of the dorsomedial hypothalamus (DMV) and the paraventricular nucleus (PVN), but was enhanced in the ventral part of the premammillary nucleus ventral part (PMV) by orexin-A (20 μg) in rotated animals. Motion sickness responses were differentially inhibited by orexin-A injection into the DMV (anorexia and hypoactivity), the PVN (conditioned gaping) and the PMV (hypothermia). SB-334867 and TCS-OX2-29 (i.c.v. and intranucleus injection) inhibited behavioural and thermal effects of orexin-A. Orexin-A (60 μg·kg −1 ) and scopolamine inhibited rotation-induced emesis and non-retching/vomiting symptoms, while orexin-A also attenuated anorexia with mild salivation in motion sickness cats. Conclusion and Implications Orexin-A might relieve motion sickness through acting on OX 1 and OX 2 receptors in various hypothalamus nuclei. Intranasal orexin-A could be a potential strategy against motion sickness.
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JOURNAL OF MEDICINAL CHEMISTRY
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2021
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IF 7.446
Hong Yao,Giuseppe Uras,Pengfei Zhang,Shengtao Xu,Ying Yin,Jie Liu,Shuai Qin,Xinuo Li,Stephanie Allen,Renren Bai,Qi Gong,Haiyan Zhang,Zheying Zhu,Jinyi Xu
Based on a multitarget strategy, a series of novel tacrine–pyrimidone hybrids were identified for the potential treatment of Alzheimer’s disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3β: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
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JOURNAL OF MEDICINAL CHEMISTRY
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2012
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IF 5.248
Yao Chen,Jianfei Sun,Lei Fang,Mei Liu,Sixun Peng,Hong Liao,Jochen Lehmann,Yihua Zhang
In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine–ferulic acid–NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 7.088
Xiaona Sun,Yujin Wang,Zhichao Lei,Shasha Yue,Li Chen,Jianbo Sun
A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase ( ee AChE IC 50 = 0.045 μM; ee BuChE IC 50 = 19.68 μM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity . Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16 , which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil . In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability.
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JOURNAL OF MEDICINAL CHEMISTRY
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2021
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IF 7.446
Qi Li,Ying Chen,Shuaishuai Xing,Qinghong Liao,Baichen Xiong,Yuanyuan Wang,Weixuan Lu,Siyu He,Feng Feng,Wenyuan Liu,Yao Chen,Haopeng Sun
Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer’s disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1–42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2021
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IF 6.514
Dan Liu,Honghua Zhang,Yuying Wang,Wencheng Liu,Gaofeng Yin,Degui Wang,Junfang Li,Tao Shi,Zhen Wang
In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N -salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS , IL-6, TNF-α, and ROS , increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aβ 1-42 . Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation , pharmacokinetics , ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.
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BIOORGANIC CHEMISTRY
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2023
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IF 5.1
Xi Zhu,Yangjing Lv,Miaoliang Fan,Jianan Guo,Yujia Zhang,Bianbian Gao,Changjun Zhang,Yuanyuan Xie
A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe 3+ = 17.07–19.52), in addition to potent inhibition of human monoamine oxidase B ( h MAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe 3+ value of 18.51, along with selective h MAO-B inhibitory activity (IC 50 = 0.79 ± 0.05 μM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 μM. Additionally, compound 11n displayed a cytoprotective effect against H 2 O 2 -induced oxidative damage. Moreover, compound 11n exhibited ideal blood–brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.
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