Shakya_2026_Mini.Rev.Med.Chem__

Neuroinflammation is a major complex reaction that causes Neurodegenerative Diseases (ND) and cognitive behavioural disorders such as Alzheimer's Disease (AD), Parkinson's disease, multiple sclerosis, and traumatic brain injury. Neuroinflammation can be regulated by different types of enzymes and proteins, including acetyl- and butyrylcholinesterases, cyclooxygenases, kinases, and the accumulation of Amyloid-beta (Abeta) plaques and hyperphosphorylated tau protein. Due to the complex physiology of enzymes and proteins, ND cannot be cured permanently yet. Therefore, we need to design and synthesise novel small molecules with high selectivity and inhibitory properties against enzymes and proteins associated with neuroinflammation. In recent decades, researchers have examined a range of different heterocyclic scaffolds for their ability to fight neuroinflammation. The 1,2,4-triazole scaffold, especially its 5-thiol and 3-thione derivatives, is a chemically flexible heterocyclic scaffold that has attracted significant attention due to its wide range of biological activities and promising drug-like properties. As a review methodology, comprehensive literature searches of the PubMed, Scopus, Web of Science (WoS), ScienceDirect, and DOAJ databases were conducted using keywords to gather information on synthesis, in vitro (IC50 values), in vivo biology, and in silico approaches related to the 1,2,4-triazole-targeted scaffold. This literature review highlights 1,2,4-triazole scaffold 5-thiol and 3-thione derivatives, potent compounds from the synthesised derivatives, presenting synthetic schemes, biological activity data, and in silico studies. Molecular docking, in silico predictions, and preclinical experiments are summarised in detail to show how they can be used in medicinal drug discovery. The goal of this review is to provide a source of information that will help with future efforts to design new neuroprotective agents based on the 1,2,4-triazole scaffold.