Exploring Thiophene-Based Pharmacophores as Emerging Therapeutics for Neurodegenerative Disorders

Neurodegenerative disorders (NDD) i.e., dementia of the Alzheimer's type, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a rising worldwide epidemic driven by aging populations and characterized by progressive neuronal impairment. In the face of symptomatic therapies, disease-modifying treatments are beyond reach, for many years, at least, owing to the multifactorial origin, including protein aggregation, oxidative stress, neuroinflammation, and neurotransmitter dysregulation. Here, we point out thiophene, a five-membered heterocyclic sulfur-containing scaffold, as an underinvestigated but highly versatile pharmacophore with great potential in therapeutics of NDD. Here, we provide a systematic review of thiophene derivatives identified between 2006 and 2024, highlighting that these compounds are capable of modulating the aggregation of amyloid-β, inhibiting acetylcholinesterase, alleviating oxidative stress, inhibiting the toxicity of α-synuclein, and restoring neurotransmitter homeostasis. Specific emphasis is placed on their structural malleability, blood-brain barrier penetrability, and multi-targeting, which collectively present advantages over traditional heterocyclic templates. Progress in the areas of structure-activity relationship (SAR)-motivated design, synthetic methods, molecular docking, and preclinical assessment is reviewed, leading to the establishment of lead thiophene scaffolds with micro or nanomolar-range activity. This review also provides future directions, such as the requirement of pharmacokinetic improvement, target verification, and translational research to bridge preclinical discoveries with clinical utility. This article collectively places thiophene derivatives as an innovative chemical platform for the design of next-generation drugs for neurodegenerative diseases.