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 ... -  《-》

Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer's disease.

The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer's disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC50) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70 % at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl3-induced zebrafish AD models and exhibited its low-toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.

Xun QQ ，Zhang J ，Li YP ，Li Y ，Ma YY ，Chen ZB ，Ding LP ，Shi XL ... -  《-》

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 ... -  《-》

Enabling Systemic Identification and Functionality Profiling for Cdc42 Homeostatic Modulators.

Malasala S ，Azimian F ，Chen YH ，Twiss JL ，Boykin C ，Akhtar SN ，Lu Q ... -  《-》