Hossein Mousavi*, Mehdi Rimaz and Behzad Zeynizadeh,
{"title":"以实用的三组分区域选择性合成类似药物的 3-芳基(或杂芳基)-5,6-二氢苯并[h]噌啉,作为潜在的非共价多靶点抑制剂防治神经退行性疾病。","authors":"Hossein Mousavi*, Mehdi Rimaz and Behzad Zeynizadeh, ","doi":"10.1021/acschemneuro.4c00055","DOIUrl":null,"url":null,"abstract":"<p >Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2<i>H</i>)-one (<b>1</b>), aryl(or heteroaryl)glyoxal monohydrates (<b>2a</b>–<b>h</b>), and hydrazine monohydrate (NH<sub>2</sub>NH<sub>2</sub>•H<sub>2</sub>O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[<i>h</i>]cinnoline derivatives (<b>3a</b>–<b>h</b>). After synthesis and characterization of the mentioned cinnolines (<b>3a</b>–<b>h</b>), the <i>in silico</i> multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various <i>Homo sapiens</i>-type enzymes, including <i>h</i>MAO-A, <i>h</i>MAO-B, <i>h</i>AChE, <i>h</i>BChE, <i>h</i>BACE-1, <i>h</i>BACE-2, <i>h</i>NQO-1, <i>h</i>NQO-2, <i>h</i>nNOS, <i>h</i>iNOS, <i>h</i>PARP-1, <i>h</i>PARP-2, <i>h</i>LRRK-2<sup>(G2019S)</sup>, <i>h</i>GSK-3β, <i>h</i>p38α MAPK, <i>h</i>JNK-3, <i>h</i>OGA, <i>h</i>NMDA receptor, <i>h</i>nSMase-2, <i>h</i>IDO-1, <i>h</i>COMT, <i>h</i>LIMK-1, <i>h</i>LIMK-2, <i>h</i>RIPK-1, <i>h</i>UCH-L1, <i>h</i>PARK-7, and <i>h</i>DHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC<sub>50</sub>, EC<sub>50</sub>, etc.) compounds. In addition, <i>in silico</i> ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (<b>3a</b>–<b>h</b>). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[<i>h</i>]cinnolines (<b>3a</b>–<b>h</b>), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases\",\"authors\":\"Hossein Mousavi*, Mehdi Rimaz and Behzad Zeynizadeh, \",\"doi\":\"10.1021/acschemneuro.4c00055\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2<i>H</i>)-one (<b>1</b>), aryl(or heteroaryl)glyoxal monohydrates (<b>2a</b>–<b>h</b>), and hydrazine monohydrate (NH<sub>2</sub>NH<sub>2</sub>•H<sub>2</sub>O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[<i>h</i>]cinnoline derivatives (<b>3a</b>–<b>h</b>). After synthesis and characterization of the mentioned cinnolines (<b>3a</b>–<b>h</b>), the <i>in silico</i> multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various <i>Homo sapiens</i>-type enzymes, including <i>h</i>MAO-A, <i>h</i>MAO-B, <i>h</i>AChE, <i>h</i>BChE, <i>h</i>BACE-1, <i>h</i>BACE-2, <i>h</i>NQO-1, <i>h</i>NQO-2, <i>h</i>nNOS, <i>h</i>iNOS, <i>h</i>PARP-1, <i>h</i>PARP-2, <i>h</i>LRRK-2<sup>(G2019S)</sup>, <i>h</i>GSK-3β, <i>h</i>p38α MAPK, <i>h</i>JNK-3, <i>h</i>OGA, <i>h</i>NMDA receptor, <i>h</i>nSMase-2, <i>h</i>IDO-1, <i>h</i>COMT, <i>h</i>LIMK-1, <i>h</i>LIMK-2, <i>h</i>RIPK-1, <i>h</i>UCH-L1, <i>h</i>PARK-7, and <i>h</i>DHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC<sub>50</sub>, EC<sub>50</sub>, etc.) compounds. In addition, <i>in silico</i> ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (<b>3a</b>–<b>h</b>). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[<i>h</i>]cinnolines (<b>3a</b>–<b>h</b>), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.</p>\",\"PeriodicalId\":13,\"journal\":{\"name\":\"ACS Chemical Neuroscience\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-04-22\",\"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.4c00055\",\"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.4c00055","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases
Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis and characterization of the mentioned cinnolines (3a–h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a–h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a–h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.
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