Searching for the Multi-Target-Directed Ligands against Alzheimer’s disease: Discovery of quinoxaline-based hybrid compounds with AChE, H3R and BACE 1 inhibitory activities

Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer’s disease therapy

“…25 Especially, an AChE and MAO-B dual inhibitor ladostigil 26 designed by Youdim had been advanced into phase II clinical trial in 2011, which confirmed the rationality and feasibility of MTDLs strategy in the treatment of AD. In continuation of our research on the design and synthesis of indole and quinoxaline derivatives as MTDLs for AD therapy, [27][28][29] we explored a new series of 2-methoxy-phenyl dimethyl-carbamate derivatives as site-activated multitarget-directed compounds.…”

Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking

“…Biologically, early QSAR studies treat AChE as a biomarker of toxicity from pesticides while investigations from later years had shifted the focus by viewing AChE as a therapeutic target for the treatment of AD. In regards to the latter point, viewpoint on targeting AChE as a single target for treating AD is starting to be replaced by the multi-target concept in which the treatment for AD can be approached by a panel of key targets (Fang et al, 2015; Huang et al, 2011). Computationally, early studies are predominantly based on simple 2D-QSAR (Mundy et al, 1978; Su & Lien, 1980) while later years started to use more sophisticated approach for understanding AChE inhibition encompassing 3D-QSAR (Deb et al, 2012; Lee & Barron, 2016; Prado-Prado et al, 2012), molecular dynamics (Shen et al, 2002), molecular docking (Lu et al, 2011; Deb et al, 2012; Giacoppo et al, 2015), pharmacophore modeling (Lu et al, 2011; Gupta & Mohan, 2014) and statistical molecular design (Andersson et al, 2014; Prado-Prado, Escobar & Garcia-Mera, 2013).…”

Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases

“…Inhibition of H3R with inverse agonists/ antagonists elevates the levels of neurotransmitters,s uch as acetylcholine (ACh), 5-HT,d opamine,o rn orepinephrine,i n the central nervous system. [11] Although compounds with multipotent profiles,c ombining H3R affinity with cholinesterase (ChE) inhibition, [12,13] antioxidant capacity, [14] or most recently with MAOinhibition, [15] have been reported, [16] MDLs that are able to simultaneously modulate H3R, MAO, and ChE have not been described to date.S uch am ultipotent profile might constitute an innovative therapeutic approach for new molecules targeting neurodegenerative diseases with multiple causes. [10] Thus the procognitive use of H3R antagonists/inverse agonists for the treatment of neurodegenerative diseases is being investigated.…”