Development of Multi-Target Directed Ligands for Neurodegenerative Disorders: A Medicinal Chemistry Approach

Abstract

Alzheimer and Parkinson disease are neurodegenerative disorders which are multi-factorial and have few treatment alternatives. Conventional single-effect medications usually cannot be effective against the rich variety of pathological methods involved, such as oxidative stress, cholinergic dysfunction, neuroinflammation, and protein aggregation. This review discusses the novel potential that Multi-Target Directed Ligands (MTDLs) offer within medicinal chemistry as a new way of working to overcome such limitations. MTDLs are single molecules designed rationally and having the capacity to affect several targets related to the disease at a time, which shows enhanced efficacy, fewer side effects, and better compliance by patients. Preclinical models of diverse MTDLs, -e.g. donepezil-built-in ferulic acid, and rasagiline hybrids have actually demonstrated cognitive andneuroprotective capability in rodent designs. Medicinal chemistry methods that were employed in thedevelopment of these ligands including pharmacophore hybridization, fragment-based design and structure-basedoptimization are also identified in the review. Despite the promising therapeutic indication associated with to theuse of MTDLs, limitations with regards to the predictability, model-predictivity of long-term toxicity data, andconventional evaluation tools remain to be the barrier towards translational efforts. The development of this fieldwill also involve interdisciplinary science, the use of enhanced AI tools in the design of drugs, and the use ofbiomarkers to perform clinical measurements to design effective, disease-modifying drugs.