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.

中文翻译：

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实用三组分区域选择性合成药物样 3-芳基（或杂芳基）-5,6-二氢苯并[h]肉啉作为潜在的非共价多靶向抑制剂来对抗神经退行性疾病

神经退行性疾病（ND）是当代社会面临的突出健康挑战之一，人们已经做出了许多努力来克服和（或）控制它。在这篇研究论文中，我们描述了 3,4-二氢萘-1(2 H )-酮 ( 1 )、芳基（或杂芳基）乙二醛一水合物 ( 2a – h )之间的实用一锅两步三组分反应，和一水合肼(NH ₂ NH ₂ ·H ₂ O)用于区域选择性制备一些3-芳基(或杂芳基)-5,6-二氢苯并[ h ]肉啉衍生物( 3a – h )。在上述 cinnolines ( 3a – h ) 的合成和表征之后，这些杂环支架的计算机多靶向抑制特性已在各种智人型酶上进行了研究，包括h MAO-A、h MAO-B、h AChE , h BChE, h BACE-1, h BACE-2, h NQO-1, h NQO-2, h nNOS, h iNOS, h PARP-1, h PARP-2, h LRRK-2 ^(G2019S) , h GSK -3β、h p38α MAPK、h JNK-3、h OGA、h NMDA 受体、h nSMase-2、h IDO-1、h COMT、h LIMK-1、h LIMK-2、h RIPK-1、h UCH- L1、h PARK-7 和h DHODH 基于分子对接研究证实了它们在神经退行性疾病 (ND) 中的功能和作用，并将获得的结果与多种已批准的药物和众所周知的药物进行了比较。与IC ₅₀、EC ₅₀等）化合物。此外，还进行了计算机ADMET 预测分析，以检查合成的杂环化合物的预期药物特性 ( 3a – h )。分子对接研究和ADMET相关数据得出的结果表明，这一系列3-芳基（或杂芳基）-5,6-二氢苯并[ h ]cinnolines ( 3a – h），特别是热门药物，确实可以转化为治疗神经退行性疾病（ND）的新药的有效核心，和/或由于具有一些可反应的位置，它们能够发生进一步的有机反应（例如交叉反应） -偶联反应），以及这些化合物的扩展（例如，使用其他类型的芳基（或杂芳基）乙二醛一水合物）为为此目的设计新颖且有效的药物提供了新途径。