{"title":"作为潜在多靶点定向配体的铬酮衍生物的体外和体内研究:利用东莨菪碱诱导的斑马鱼模型改善认知。","authors":"Naveen Kumar, Kailash Jangid, Vishal Kumar, Ravi Prakash Yadav, Jayapriya Mishra, Shubham Upadhayay, Vinay Kumar, Bharti Devi, Vijay Kumar, Ashish Ranjan Dwivedi, Puneet Kumar, Somesh Baranwal, Jasvinder Singh Bhatti and Vinod Kumar*, ","doi":"10.1021/acschemneuro.4c00007","DOIUrl":null,"url":null,"abstract":"<p >Alzheimer’s disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer’s disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., <b>VN-3</b>, <b>VN-14</b>, and <b>VN-19</b> were identified that displayed remarkable activities against different targets. These compounds displayed IC<sub>50</sub> values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC<sub>50</sub> values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. <b>VN-3</b> displayed potent activity against self-induced Aβ<sub>1–42</sub> aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound <b>VN-19</b> exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ<sub>1–42</sub> enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. <b>VN-19</b> was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, <b>VN-3</b>, <b>VN-14</b>, and <b>VN-19</b> were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model\",\"authors\":\"Naveen Kumar, Kailash Jangid, Vishal Kumar, Ravi Prakash Yadav, Jayapriya Mishra, Shubham Upadhayay, Vinay Kumar, Bharti Devi, Vijay Kumar, Ashish Ranjan Dwivedi, Puneet Kumar, Somesh Baranwal, Jasvinder Singh Bhatti and Vinod Kumar*, \",\"doi\":\"10.1021/acschemneuro.4c00007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Alzheimer’s disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer’s disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., <b>VN-3</b>, <b>VN-14</b>, and <b>VN-19</b> were identified that displayed remarkable activities against different targets. These compounds displayed IC<sub>50</sub> values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC<sub>50</sub> values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. <b>VN-3</b> displayed potent activity against self-induced Aβ<sub>1–42</sub> aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound <b>VN-19</b> exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ<sub>1–42</sub> enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. <b>VN-19</b> was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, <b>VN-3</b>, <b>VN-14</b>, and <b>VN-19</b> were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.</p>\",\"PeriodicalId\":13,\"journal\":{\"name\":\"ACS Chemical Neuroscience\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-05-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Chemical Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acschemneuro.4c00007\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acschemneuro.4c00007","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model
Alzheimer’s disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer’s disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aβ1–42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ1–42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research