Rational design, synthesis and computational studies of multi-targeted anti-Alzheimer's agents integrating coumarin scaffold.

The traditional theory of "one drug, one target, one illness" has come under scrutiny owing to the multifactorial nature of Alzheimer's disease (AD) and the failure of most of its medications, therefore multi-target directed ligands (MTDLs) are prospective therapeutics for AD. In the present study, we synthesized novel series of coumarin derivatives and assessed their inhibitory actions against hAChE, hBuChE, GSK-3β, tau protein and Aβ aggregation. Compounds 6c and 6h stood out among the others with their multifunctional profile. With IC50 values of 28.88 and 26.03 nM, respectively, compounds 6c and 6h showed outstanding activity as hAChE inhibitors and demonstrated good inhibitory activity against hBuChE with IC50 values of 103.90 and 90.09 nM along with appropriate action against GSK-3β in nanomolar range. Also, both compounds 6c and 6h were found to outperform the reported anti-AD donepezil as tau protein aggregation and amyloid aggregation (Aβ) inhibitors as well as low cytotoxicity on healthy neuroblastoma SHSY5Y and hepatic THLE2 cells. Kinetic analysis and docking studies indicated hAChE dual site (mixed) inhibitory effect of compound 6h. Both compounds 6c and 6h complied with Lipinski's rule of five and were virtually able to cross the BBB. All the data suggested that compounds 6c and 6h have potential as a multifunctional therapy for AD.

Abd El-Mageed MMA ，Fattah Ezzat MA ，Moussa SA ，Abdel-Aziz HA ，Elmasry GF ... -  《-》

Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3β/Aβ aggregation inhibitor and anti-Alzheimer's agent.

Sukanya S ，Bellver-Sanchis A ，Singh Choudhary B ，Kumar S ，Pérez B ，Leandro Martínez Rodríguez A ，Brea J ，Griñán-Ferré C ，Malik R ... -  《-》

Discovery of novel quinolin-2-one derivatives as potential GSK-3β inhibitors for treatment of Alzheimer's disease: Pharmacophore-based design, preliminary SAR, in vitro and in vivo biological evaluation.

Recently, glycogen synthase kinase-3β (GSK-3β) has been considered as a critical factor implicated in Alzheimer's disease (AD). In a previous work, a 3D pharmacophore model for GSK-3β inhibitors was created and the results suggested that derivative ZINC67773573, VIII, may provide a promising lead for developing novel GSK-3β inhibitors for the AD's treatment. Consequently, in this work, novel series of quinolin-2-one derivatives were synthesized and assessed for their GSK-3β inhibitory properties. In vitro screening identified three compounds: 7c, 7e and 7f as promising GSK-3β inhibitors. Compounds 7c, 7e and 7f were found to exhibit superior inhibitory effect on GSK-3β with IC50 value ranges between 4.68 ± 0.59 to 8.27 ± 0.60 nM compared to that of staurosporine (IC50 = 6.12 ± 0.74 nM). Considerably, compounds 7c, 7e and 7f effectively lowered tau hyperphosphorylated aggregates and proving their safety towards the SH-SY5Y and THLE2 normal cell lines. The most promising compound 7c alleviated cognitive impairments in the scopolamine-induced model in mice. Compound 7c's activity profile, while not highly selective, may provide a starting point and valuable insights into the design of multi-target inhibitors. According to the ADME prediction results, compounds 7c, 7e and 7f followed Lipinski's rule of five and could almost permeate through the BBB. Molecular docking simulations showed that these compounds are well accommodated in the ATP binding site interacting by its quinoline-2-one ring through hydrogen bonding with the key amino acids Asp133 and Val135 at the hinge region. The findings of this study suggested that these new compounds may have potential as anti-AD drugs targeting GSK-3β.

Abdo Moustafa E ，Abdelrasheed Allam H ，Fouad MA ，El Kerdawy AM ，Nasser Eid El-Sayed N ，Wagner C ，Abdel-Aziz HA ，Abdel Fattah Ezzat M ... -  《-》

Promising thiazolidinedione-thiazole based multi-target and neuroprotective hybrids for Alzheimer's disease: Design, synthesis, in-vitro, in-vivo and in-silico studies.

Alzheimer's disease (AD) is marked by low neurotransmitter levels, inflammation, increased oxidative stress, and the aggregation of amyloid-β and tau proteins. The development of hybrid compounds acting as multi-target-directed ligands (MTDLs) is a novel and contemporary approach in Alzheimer's disease therapeutics. The objective of our current research focuses on identifying compounds with balanced, even moderate inhibition potential against multiple targets associated with cholinergic deficit and neuroinflammation. Inspired by our previous study, the thiazolidinedione-thiazole-based framework has been employed to design and synthesize a series of new hybrids. The inhibitory effects of the synthesized compounds on selected enzymes were investigated by employing in-vitro methods. The synergistic inhibition of acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), β-secretase (BACE-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) by compound 49 is believed to have a more potent effect in treating Alzheimer's disease. Enzyme kinetic studies and their effect on substrate-enzyme interactions of the compounds with significant inhibitory potency for AChE and MAO-B were also investigated. Central nervous system (CNS) penetration was determined using in-vitro PAMPA assay. A neurotoxicity test on neuroblastoma cell lines (SH-SY5Y) showed that the compounds were non-toxic. Compound 49 showed an excellent neuroprotective effect by significantly reducing H2O2-induced oxidative stress. Antioxidant enzymes were studied in an in-vivo experiment in the brains of male BALB/c mice. Compound 49 showed its ability to reduce the oxidative stress. Furthermore, molecular docking studies and 100 ns MD simulations performed on the AChE, MAO-B, and COX-2 ligand-protein complexes revealed stable conformations of the ligand-protein interactions throughout the simulations.

Hussain F ，Tahir A ，Rehman HM ，Wu Y ，Shah M ，Rashid U ... -  《-》

Carbon dots as dual inhibitors of tau and amyloid-beta aggregation for the treatment of Alzheimer's disease.

Zhang W ，Smith N ，Zhou Y ，McGee CM ，Bartoli M ，Fu S ，Chen J ，Domena JB ，Joji A ，Burr H ，Lv G ，Cilingir EK ，Bedendo S ，Claure ML ，Tagliaferro A ，Eliezer D ，Veliz EA ，Zhang F ，Wang C ，Leblanc RM ... -  《-》