抗阿尔茨海默病噻唑衍生物的设计策略及构效关系研究进展

doi:10.3969/j.issn.1000-1565.2024.01.006

摘要/Abstract

摘要： 噻唑是一种五元含硫、氮杂环化合物,由于其特殊的结构和电子性质以及具有的多种生物学活性,已成为药物化学领域中广泛运用的化学骨架之一.在过去的几十年里,噻唑及其衍生物在抗阿尔茨海默病的研究中展现出极大的潜力,其衍生物的化学结构及设计策略和抗阿尔茨海默病的活性密切相关.本文从阿尔茨海默病潜在的靶点出发,基于以乙酰胆碱酯酶为主导的单靶点或者多靶点策略,综述了近年来具有抗阿尔茨海默病活性的噻唑衍生物的设计策略及构效关系研究进展.

关键词: 噻唑衍生物, 阿尔茨海默病, 设计策略, 构效关系

Abstract: Thiazole is a five-membered sulfur-containing and nitrogen heterocyclic compound, which has become one of the widely used chemical frameworks in the field of medicinal chemistry due to its special structure and electronic properties and a variety of biological activities. In the past few decades, thiazole and its derivatives have shown great potential in anti-Alzheimers research, and the chemical structure and design strategy of its derivatives are closely related to anti-Alzheimers activity. Starting from the potential targets of Alzheimers disease, this article reviewed the design strategies and structure-activity research progress of thiazole derivatives with anti-Alzheimers activity in recent years based on acetylcholinesterase dominated single-target or multi-target strategies.

Key words: thiazole derivatives, Alzheimers disease, design strategy, structure-activity relationship

中图分类号:

R914.5

史大华,邹靖培,张笑清,张钊源, 韩抒彤. 抗阿尔茨海默病噻唑衍生物的设计策略及构效关系研究进展[J]. 河北大学学报(自然科学版), 2024, 44(1): 42-49.

SHI Dahua, ZOU Jingpei, ZHANG Xiaoqing, ZHANG Zhaoyuan, HAN Shutong. Research progress on design strategies and structure-activity relationship of anti-Alzheimer thiazole derivatives[J]. Journal of Hebei University(Natural Science Edition), 2024, 44(1): 42-49.

参考文献

[1] OKELLO E J, MATHER J. Comparative kinetics of acetyl- and butyryl-Cholinesterase inhibition by green tea catechins|relevance to the symptomatic treatment of Alzheimers disease[J]. Nutrients, 2020,12(4). DOI: 10.3390/nu12041090.
[2] JAHN H. Memory loss in Alzheimers disease[J]. Dialogues in Clinical Neuroscience, 2013,15(4):445-454. DOI: 10.31887/DCNS.2013.15.4/hjahn.
[3] FORSTL H, KURZ A. Clinical features of Alzheimers disease[J]. European Archives of Psychiatry and Clinical Neuroscience, 1999,249(6):288-290. DOI: 10.1007/s004060050101.
[4] TAHAMI M A, BYRNES M J, WHITE L A, et al. The humanistic and economic burden of Alzheimers disease[J]. Neurology and Therapy, 2022,11(2):525-551. DOI: 10.1007/s40120-022-00335-x.
[5] SCHNEIDER L S. A critical review of cholinesterase inhibitors as a treatment modality in Alzheimers disease[J]. Dialogues in Clinical Neuroscience, 2000,2(2):111-128. DOI: 10.31887/DCNS.2000.2.2/lschneider.
[6] BARAGE S H, SONAWANE K D. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimers disease[J]. Neuropeptides, 2015,52:1-18. DOI: 10.1016/j.npep.2015.06.008.
[7] MACCIONI R B, FARIAS G, MORALES I, et al. The revitalized tau hypothesis on Alzheimers disease[J]. Archives of Medical Research, 2010,41(3):226-231. DOI: 10.1016/j.arcmed.2010.03.007.
[8] BAI R, GUO J, YE X Y, et al. Oxidative stress: The core pathogenesis and mechanism of Alzheimers disease[J]. Ageing Research Reviews, 2022,77:101619. DOI: 10.1016/j.arr.2022.101619.
[9] AYTON S, LEI P, BUSH A I. Metallostasis in Alzheimers disease[J]. Free Radical Biology & Medicine, 2013,62:76-89. DOI: 10.1016/j.freeradbiomed.2012.10.558.
[10] HENEKA M T, OBANION M K, TERWEL D, et al. Neuroinflammatory processes in Alzheimers disease[J]. Journal of Neural Transmission, 2010,117(8):919-947. DOI: 10.1007/s00702-010-0438-z.
[11] LIU Z, ZHANG A, SUN H, et al. Two decades of new drug discovery and development for Alzheimers disease[J]. RSC Advances, 2017,7(10):6046-6058. DOI: 10.1039/C6RA26737H.
[12] WATKINS P B, ZIMMERNAN H J, KNAPP M J, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimers disease[J]. JAMA, 1994,271(13):992-998. DOI: 10.1001/jama.1994.03510370044030.
[13] JU Y, TAM K Y. Pathological mechanisms and therapeutic strategies for Alzheimers disease[J]. Neural Regeneration Research, 2022,17(3):543-549. DOI: 10.4103/1673-5374.320970.
[14] DIGHE S N, DEORA G S, DE LA MORA E, et al. Discovery and structure-activity relationships of a highly selective butyrylcholinesterase inhibitor by structure-based virtual screening[J]. Journal of Medicinal Chemistry, 2016,59(16):7683-7689. DOI: 10.1021/acs.jmedchem.6b00356.
[15] LI Q, XING S, CHEN Y, et al. Discovery and biological evaluation of a novel highly potent selective butyrylcholinesterase inhibitor[J]. Journal of Medicinal Chemistry, 2020,63(17):10030-10044. DOI: 10.1021/acs.jmedchem.0c01129.
[16] RANA M, PAREEK A, BHARDWAJ S, et al. Aryldiazoquinoline based multifunctional small molecules for modulating Aβ42 aggregation and cholinesterase activity related to Alzheimers disease[J]. RSC Advances, 2020,10(48):28827-28837. DOI: 10.1039/D0RA05172A.
[17] SANG Z, WANG K, DONG J, et al. Alzheimers disease: Updated multi-targets therapeutics are in clinical and in progress[J]. European Journal of Medicinal Chemistry, 2022,238:114464. DOI: 10.1016/j.ejmech.2022.114464.
[18] GUMUS M, YAKAN M, KOCA I. Recent advances of thiazole hybrids in biological applications[J]. Future Medicinal Chemistry, 2019,11(15):1979-1998. DOI: 10.4155/fmc-2018-0196.
[19] 冯媛媛,宋梦秋,武文龙,等.2-苯基噻唑-香豆素衍生物的合成与抗肿瘤活性研究[J].化学研究与应用, 2022,34(6):1362-1368. DOI: 10.3969/j.issn.1004-1656.2022.06.018.
[20] 马太贵,李心怡,周阿康, 等.芳基噻唑胺类化合物合成及其抑菌活性研究[J].化学研究与应用, 2023,35(1):107-112. DOI: 10.3969/j.issn.1004-1656.2023.01.014.
[21] 刘大川,吴成柱,霍强,等.二甲吡唑联苯并噻唑的合成及抗惊厥活性研究[J].广州化工, 2019,47(12):53-56. DOI: 10.3969/j.issn.1001-9677.2019.12.023.
[22] 张强强,刘新泳.新型4-噻唑烷酮衍生物及其抗病毒活性研究进展[J].药学进展, 2012,36(9):394-399. DOI: 10.3969/j.issn.1001-5094.2012.09.002.
[23] QIAN J J, ZOU J P, LIU S M, et al. Synthesis, characterization, crystal structure, and cholinesterase inhibitory activity of 2-phenylthiazole derivatives[J]. Journal of Molecular Structure, 2023,1282:135248. DOI: 10.1016/j.molstruc.2023.135248.
[24] MATSUNAGA Y, TANAKA T, YOSHINAGA K, et al. Acotiamide hydrochloride(Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride[J]. Journal of Pharmacology and Experimental Therapeutic, 2011,336(3):791-800. DOI: 10.1124/jpet.110.174847.
[25] 张蝶.地黄饮子对APP/PS1小鼠突触功能及胆碱能系统的保护机制[D].北京中医药大学, 2019.
[26] ZOU J P, QIAN J J, LIU S M, et al. Design, synthesis, biological evaluation and molecular dynamics simulations study of genistein-O-1,3,5-Triazine derivatives as multifunctional anti-alzheimer agents[J]. ChemistrySelect, 2022,7(47):e202203997. DOI: 10.1002/slct.202203997.
[27] 栾剑,杨心悦.阿尔茨海默病的发病机制和药物研发进展[J].中国合理用药探索, 2022,19(5):11-16. DOI: 10.3969/j.issn.2096-3327.2022.05.003.
[28] XU Y, JIAN M M, HAN C, et al. Design, synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors[J]. Bioorganic & Medicinal Chemistry Letters, 2020,30(6):126985. DOI: 10.1016/j.bmcl.2020.126985.
[29] 马正月,杨琦,张元功,等.N-酰基-4-苯基噻唑-2-胺类衍生物的设计、合成及其乙酰胆碱酯酶抑制活性研究[J].药学学报,2014,49(6):813-818.DOI:10.16438/j.0513-4870.2014.06.019.
[30] SONMEZ F,ZENGIN KURT B,GAZIOGLU I, et al. Design synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors[J].Journal of Enzymeinhibition and Medicinal Chemistry, 2016, 32(1): 285-297.DOI: 10.1080/14756366.2016.1250753.
[31] YIN L, CHENG F C, LI Q X, et al. Synthesis and biological evaluation of novel C1-glycosyl thiazole derivatives as acetylcholinesterase inhibitors[J]. Journal of chemical research, 2016,40(9):545-548. DOI: 10.3184/174751916X14711768865726.
[32] WANG Y X, LIU S H, SHAO Z B, et al. Synthesis and anti-acetylcholinesterase activities of novel glycosyl coumarylthiazole derivatives[J]. Journal of chemical research, 2021,45(5-6):359-364. DOI: 10.1177/1747519820948358.
[33] LIU H, QU Y, WANG X. Amyloid β-targeted metal complexes for potential applications in Alzheimers disease[J]. Future Medicinal Chemistry, 2018,10(6):679-701. DOI: 10.4155/fmc-2017-0248.
[34] VALENSIN D, GABBIANI C, MESSORI L. Metal compounds as inhibitors of β-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimers disease[J]. Coordination Chemistry Reviews, 2012,256(19-20):2357-2366. DOI: 10.1016/j.ccr.2012.04.010.
[35] HUFFMAN S E, YAWSON G K, FISHER S S, et al. Ruthenium(iii)complexes containing thiazole-based ligands that modulate amyloid-β aggregation[J]. Metallomics, 2020,12(4):491-503. DOI: 10.1039/d0mt00054j.
[36] ALVAREZ A, OPAZO C, ALARCON R, et al. Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils[J]. Journal of Molecular Biology, 1997,272(3):348-361. DOI: 10.1006/jmbi.1997.1245.
[37] SAG ˇLIK B N, LEVENT S, OSMANIYE D, et al. Design, synthesis, and biological activity evaluation of new eonepezil-like compounds bearing thiazole ring for the treatment of Alzheimer’s disease[J]. Crystals, 2020,10(8):637. DOI: 10.3390/cryst10080637.
[38] KARACA S, OSMANIYE D, SAGˇLIK B N, et al. Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimers disease[J]. RSC Advances, 2022,12(36):23626-23636. DOI: 10.1039/D2RA03803J.
[39] MEKKY A E M, SANAD S M H, El-IDREESY T T. New thiazole and thiazole-chromene hybrids possessing morpholine units: Piperazine-mediated one-pot synthesis of potential acetylcholinesterase inhibitors[J]. Synthetic Communications, 2021,51(21):3332-3344. DOI: 10.1080/00397911.2021.1970774.
[40] GHOTBI G, MAHDAVI M, NAJAFI Z, et al. Design, synthesis, biological evaluation, and docking study of novel dual-acting thiazole-pyridiniums inhibiting acetylcholinesterase and beta-amyloid aggregation for Alzheimers disease[J]. Bioorganic Chemistry, 2020,103:104186. DOI: 10.1016/j.bioorg.2020.104186.
[41] KUMAR H, GOYAL A, KUMAR N, et al. Design, Synthesis, and biological evaluation of pyrazolo-benzothiazole derivatives as a potential therapeutic agent for the treatment of Alzheimer’s disease[J]. Medicinal Chemistry Research, 2022,31(11):1931-1947. DOI: 10.1007/s00044-022-02953-4. (