Lipoic Acid Scaffold Applications in the Design of Multitarget-Directed Ligands Against Alzheimer's Disease Publisher Pubmed



Manavi MA¹ ; Nourhashemi M^{2, 3} ; Emami S³ ; Fathian Nasab MH¹ ; Dehnavi F³ ; Kucukkilinc TT⁴ ; Foroumadi A^{1, 2} ; Sharifzadeh M⁵ ; Khoobi M^{1, 6} Show Affiliations
Source: Bioorganic Chemistry Published:2025

Abstract

Alzheimer's disease (AD) is becoming a fast-growing public health problem which can result in psychological problems as well as loss of speech, language, short-term memory, and motor coordination. Many medications were developed and produced to treat AD, however due to the complexity of the pathology involved in the illness, many of these medications often failed in clinical or preclinical studies. The main issue with the current anti-AD medications is their low efficacy since they use a single target. Multi-target-directed ligands (MTDLs) based on “one molecule; multiple targets” have been introduced to address these two fundamental issues. MTDLs have demonstrated improved efficacy and safety since they regulate many biological targets simultaneously. Alpha-lipoic acid (LA), a natural molecule with distinct properties, is a viable scaffold for developing new MTDLs in treating many neurodegenerative diseases, particularly AD. It is a key mitochondrial enzymes’ cofactor and an organic molecule with disulfide functionality. It also has potent antioxidant characteristics that enhance mitochondrial activity. Considering the neuroprotective and anti-inflammatory effects of LA, various hybrids of LA with tacrine, rivastigmine, coumarin and chromone, ibuprofen, melatonin, niacin have been synthesized and biologically evaluated as the MTDLs. In this article, we review the design of LA-based hybrids or conjugates, their biological activities, and structure–activity relationship studies, to develop new MTDLs in the field of AD pharmacotherapy. © 2025 Elsevier Inc.