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阿尔茨海默病的发病机制与 1,2,3-三唑骨架在药物研发中的多样性:设计策略、结构见解和治疗潜力。

Pathogenesis of Alzheimer's Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential.

机构信息

Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.

University School of Business, Chandigarh University, Mohali, Punjab 140413, India.

出版信息

ACS Chem Neurosci. 2023 Sep 20;14(18):3291-3317. doi: 10.1021/acschemneuro.3c00393. Epub 2023 Sep 8.

Abstract

Alzheimer's disease is a most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently available drugs only slow the progression of this disease rather than provide proper containment. Identification of multiple targets responsible for this disease in the last three decades established it as a multifactorial neurodegenerative disorder that needs novel multifunctional agents for its management and the possible reason for the failure of currently available single target clinical drugs. 1,2,3-Triazole is a miraculous nucleus in medicinal chemistry and the first choice for development of multifunctional hybrid molecules. Apart from that, it is an integral component of various drugs in clinical trials as well as in clinical practice. This review is focused on the pathogenesis of Alzheimer's disease and 1,2,3-triazole containing derivatives developed in recent decades as potential anti-Alzheimer's agents. The review will provide (A) precise insight of various established targets of Alzheimer's disease including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, and reactive oxygen species hypothesis and (B) design hypothesis, structure-activity relationships, and pharmacological outcomes of 1,2,3-triazole containing multifunctional anti-Alzheimer's agents. This review will provide a baseline for various research groups working on Alzheimer's drug development in designing potent, safer, and effective multifunctional anti-Alzheimer's candidates of the future.

摘要

阿尔茨海默病是全球最常见的痴呆症形式,目前对医疗保健系统构成重大挑战。目前可用的药物只能减缓这种疾病的进展,而不能进行适当的控制。在过去三十年中,确定了导致这种疾病的多个靶点,将其确立为一种多因素神经退行性疾病,需要新型多功能药物来治疗,这可能也是目前单一靶点临床药物失败的原因。1,2,3-三唑是药物化学中的神奇核心,是开发多功能杂合分子的首选。除此之外,它还是临床试验以及临床实践中多种药物的组成部分。这篇综述重点介绍了阿尔茨海默病的发病机制,以及近几十年来开发的含有 1,2,3-三唑的衍生物作为潜在的抗阿尔茨海默病药物。综述将提供(A)阿尔茨海默病的各种既定靶点的精确见解,包括胆碱能、淀粉样蛋白、tau、单胺氧化酶、谷氨酸、钙和活性氧假说,以及(B)设计假说、构效关系和含 1,2,3-三唑的多功能抗阿尔茨海默病药物的药理结果。这篇综述将为从事阿尔茨海默病药物开发的各个研究小组提供一个基础,以便在未来设计出更有效、更安全的多功能抗阿尔茨海默病候选药物。

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