Therapeutic role of NLRP3 inflammasome inhibitors against Alzheimer’s disease

• Published in: Bioorganic chemistry 2024-12, Vol.153, p.107912, Article 107912
• Main Authors: Tantra, Tanmoy, Rahaman T. A., Abdul, Nandini, Chaudhary, Sandeep
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta (Aβ); Animals; Humans; IL-1β; Inflammasome; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inhibitors; Pro-cytokines; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107912

[Display omitted] •NLRP3 regulates inflammasome pathways.•Targeting NLPR3 is a promising strategy for Alzheimer’s disease (AD).•NLRP3 inflammasome inhibition by natural products and small compounds is discussed.•Synthetic strategies and structure–activity relationship (SAR) were discussed. The NLRP3 inflammasome is a multiprotein complex that plays a vital role in regulating inflammatory signaling and the innate immune system. Activation of NLRP3 by accumulation of Aβ leads to its oligomerization and the activation of caspase-1, resulting in the secretion of pro-cytokines such as IL-18 and IL-1β. These pro-cytokines can contribute to cognitive impairment and neurodegeneration. The activation of NLRP3 is associated with neuroinflammation in animal models of Alzheimer’s disease (AD). Therefore, the NLRP3 inflammasome is considered a potential therapeutic target for AD. Various natural and synthetic molecules have gained attention as NLRP3 inhibitors against AD. In this review, we will summarize the sources, chemical structures, synthesis, and biological activity of NLRP3 inhibitors as anti-Alzheimer’s agents. Additionally, we will critically analyze the structure–activity relationship (SAR) of NLRP3 inhibitors. This detailed examination of the SAR-based investigation of NLRP3 inhibitors and their derivatives offers insights into the design and development of novel NLRP3 inhibitors as anti-Alzheimer’s agents. It is expected that this review will assist researchers in developing innovative and effective NLRP3 inhibitors for the treatment of AD.