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Multicomponent Reactions for Multitargeted Compounds for Alzheimer`s Disease
Lhassane Ismaili1, Maria do Carmo Carreiras2
1Neurosciences Integratives et Cliniques EA 481, Laboratoire de Chimie Organique et Therapeutique, UFR SMP, 19 rue Ambroise Pare, Universite Bourgogne Franche-Comte, F25000 Besancon, France.
Abstract:
Alzheimer's Disease (AD) is a multifactorial and fatal neurodegenerative disorder affecting around 35 million people worldwide, which is characterized by decline of cholinergic function, deregulation of amyloid beta (Aβ) oligomers formation and Aβ fibril deposition. Multi-Target- Directed Ligands (MTDLs) have emerged as an original strategy for developing new therapeutic agents on AD. Multicomponent Reactions (MCRs) are a useful alternative to sequential multistep syntheses, allowing scaffold diversity and a rapid and easy access to biologically relevant compounds. The biological diversity of MCRs is very rich providing great possibilities for researchers interested in bioactive small molecular weight compounds. Since the MTDL strategy has been used to develop compounds endowed with the capacity to interact with different targets, versatile compound libraries may be obtained by MCRs according to the well established features of each target. Thus, either MTDLs or monotarget compounds have been developed by MCRs to address different factors implicated in AD. This work focuses on antioxidants, calcium channel modulators, both AChE and BuChE inhibitors, BACE1 inhibitors, and modulators of the nuclear factor (erythroid-derived 2)-like 2. First, we discuss the Biginelli reaction and its use for developing new interesting compounds for AD, followed by the contribution of Ugi reaction and, finally, the interest of other MCRs in the same topic.
Insights
Multi-Target-Directed Ligands (MTDLs) synthesized via Multicomponent Reactions (MCRs) offer a promising strategy for Alzheimer
Area of Science:
- Neuroscience
- Medicinal Chemistry
- Organic Synthesis
Background:
- Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cholinergic decline and amyloid-beta pathology.
- Multi-Target-Directed Ligands (MTDLs) represent a novel therapeutic strategy for complex diseases like AD.
- Multicomponent Reactions (MCRs) provide efficient synthesis of diverse molecular scaffolds for drug discovery.
Purpose of the Study:
- To explore the application of MCRs in synthesizing MTDLs for Alzheimer's Disease.
- To review MCRs, including Biginelli and Ugi reactions, for developing AD therapeutic agents.
- To highlight MCRs' potential in creating compound libraries targeting various AD-related pathways.
Main Methods:
- Literature review focusing on MCRs applied to Alzheimer's Disease drug discovery.
- Analysis of MTDLs developed using MCRs targeting key AD pathways.
- Discussion of specific MCRs like Biginelli and Ugi reactions in the context of AD.
Main Results:
- MCRs enable rapid and diverse synthesis of compounds with potential therapeutic value for AD.
- MTDLs developed via MCRs can simultaneously target multiple AD-related mechanisms.
- Specific MCRs have been successfully employed to generate inhibitors of AChE, BuChE, BACE1, and modulators of other AD targets.
Conclusions:
- MCRs are powerful tools for generating MTDLs and diverse compound libraries for Alzheimer's Disease research.
- The MTDL strategy, facilitated by MCRs, holds significant promise for developing novel Alzheimer's therapies.
- Further exploration of MCRs can accelerate the discovery of effective treatments for Alzheimer's Disease.