Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Duarte, Yorley; Fonseca, André; Gutiérrez, Margarita; Adasme‐Carreño, Francisco; Muñoz‐Gutierrez, Camila; Alzate‐Morales, Jans; Santana, Lourdes; Uriarte, Eugenio; Álvarez, Rocío; Matos, Maria João
• Is Part Of: ChemistrySelect. Volume 4:Issue 2(2019)
• Page Start: 551
• Page End: 558
• Publication Date: 2019-01-15
• Subjects: Drug design -- Coumarin-quinoline hybrids -- Acetyl/butyrylcholinesterases' inhibitors -- Iron chelating agents -- Neuroprotective agents.; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201803222
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, presenting the most devastating consequences on human health and life quality. Coumarin‐quinoline hybrids were synthesized following a very efficient and versatile strategy. Small structural variations contributed to dual acetyl/butyrylcholinesterases (AChE/BuChE) activity or selectivity towards one of these enzymes. In addition, some of the studied compounds are interesting iron chelators, presenting a tendency to be neuroprotective. Moreover, the compounds are not cytotoxic for SH‐SY5Y neuroblastoma cells. Compound 9c proved to be the most interesting compound of the studied series. This compound is selective against AChE and proved to be an excellent iron chelating agent (iron chelation at 100 μM=72.87%). Molecular docking studies were performed to establish the nature of the interaction between the studied compounds and the binding pockets, leading to a rationalization of structure–activity relationships. Compound 9c forms a well‐defined π‐stacking interaction with Phe330 and interacts with Tyr121 residue via a hydrogen bond, while the inactive compounds cannot establish these interactions. Important preliminary results against different targets, as well as some structure–activity relationships, were concluded from the experimental results. Abstract : The inhibition of acetyl/butyrylcholinesterases is one of the well‐stablished targets for the treatment of Alzheimer's disease. In addition, iron chelators have been shown neuroprotective effects in patients. Here we show the computer‐assisted design of twenty new coumarin‐quinoline hybrids as multitarget compounds. Moreover, the selectivity profile was predicted computationally by molecular docking studies. This approach allowed a better understanding of the structure‐activity relationships observed for these new hybrids in order to optimize the design of new and more potent multitarget compounds.