Small Multitarget Molecules Incorporating the Enone Moiety

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-01, Vol.24 (1), p.199
• Main Authors: Liargkova, Thalia, Eleftheriadis, Nikolaos, Dekker, Frank, Voulgari, Efstathia, Avgoustakis, Constantinos, Sagnou, Marina, Mavroidi, Barbara, Pelecanou, Maria, Hadjipavlou-Litina, Dimitra
• Format: Article
• Language: English
• Subjects: acetylcholinesterase inhibitors; Alzheimer; Alzheimer Disease - drug therapy; Alzheimer's disease; Antioxidants; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - therapeutic use; bis-chalcones; bis-ethers; Blood-brain barrier; Blood-Brain Barrier - drug effects; chalcones; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - therapeutic use; Cholinesterase; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - therapeutic use; Circular Dichroism; Cytotoxicity; Dichroism; Enzymes; Humans; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Lipoxygenase; lipoxygenase inhibitors; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - therapeutic use; Liquid oxygen; Medical research; Molecular Docking Simulation; Molecular weight; multitarget; Oxidation; Oxidative stress; Pathology; Peroxidation; Protein Aggregation, Pathological - drug therapy; Structure-Activity Relationship; β-amyloid peptide
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24010199

Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since "one drug-one target" therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the -etherified -chalcone skeleton. Furthermore, the synthesized molecules were evaluated for their cytotoxicity. Simple chalcone presents significant inhibitory activity against the 15-human LOX with an IC value 9.5 µM, interesting anti-AChE activity, and anti-lipid peroxidation behavior. -etherified chalcone is the most potent inhibitor of AChE within the -etherified -chalcones followed by . -chalcones and were found to combine anti-LOX, anti-AchE, and anti-lipid peroxidation activities. It seems that the anti-lipid peroxidation activity supports the anti-LOX activity for the significantly active -chalcones. Our circular dichroism (CD) study identified two structures capable of interfering with the aggregation process of Aβ. Compounds and display additional protective actions against Alzheimer's disease (AD) and add to the pleiotropic profile of the chalcone derivatives. Predicted results indicate that the majority of the compounds with the exception of (144 Å) can cross the Blood Brain Barrier (BBB) and act in CNS. The results led us to propose new leads and to conclude that the presence of a double enone group supports better biological activities.