Phthalimide-(N-alkylbenzylamine) cysteamide hybrids as multifunctional agents against Alzheimer's disease: Design, synthesis, and biological evaluation.

The complex pathogenesis of Alzheimer's disease (AD) calls for multi-target approach for disease treatment. Herein, based on the MTDLs strategy, a series of phthalimide-(N-alkylbenzylamine) cysteamide hybrids were designed, synthesized, and investigated in vitro for the purpose. Most of the target compounds were found to be potential multi-target agents. In vitro results showed that compound 9e was the representative compound in this series, endowed with high EeAChE and HuAChE inhibitory potency (IC50  = 1.55 µm and 2.23 µm, respectively), good inhibitory activity against self-induced Aß1-42 aggregation (36.08% at 25 µm), and moderate antioxidant capacity (ORAC-FL value was 0.68 Trolox equivalents). Molecular docking studies rationalized the binding mode of 9e in both PAS and CAS of AChE. Moreover, 9e displayed excellent ability to against H2 O2 -induced PC12 cell injury and penetrate BBB. Overall, these results highlighted that compound 9e was an effective and promising multi-target agent for further anti-AD drug development.

Design, synthesis and evaluation of pterostilbene ß-amino alcohol derivatives as multifunctional agents for Alzheimer's disease treatment.

A series of pterostilbene ß-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC50 = 24.04 µM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. Moreover, 5f also showed self-induced Aß1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.

Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aß1-42 aggregation, Cu2+-induced Aß1-42 aggregation, human AChE-induced Aß1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aß1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.

Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-ß-amyloid aggragation and neuroprotective properties for the treatment of Alzheimer's disease.

A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC50 = 0.00878 ± 0.0002 µM, 0.0212 ± 0.006 µM and 0.0371 ± 0.004 µM, respectively). Moreover, 7d displayed high antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu2+-induced Aß1-42 aggregation inhibitory potency and high BBB permeability. These multifunctional properties highlight 7d as promising candidate for further studies directed to the development of novel drugs against AD.

Design, synthesis, and biological evaluation of scutellarein carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

A series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed drug design strategy for treatment of Alzheimer's disease. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metals chelation, and neuroprotective effects against hydrogen peroxide-induced PC12 cell injury were evaluated in vitro. The preliminary results indicated that compound 7b exhibited good inhibitory potency toward AChE and BuChE with IC50 values of 1.2 ± 0.03 µm and 22.1 ± 0.15 µm, respectively, possessed the strong antioxidant potency (10.3 trolox equivalents), as well as acted as a selective metal chelator and neuroprotective agent. Furthermore, 7b could improve memory impairment induced by scopolamine, ethanol, and sodium nitrite using the step-down passive avoidance task in vivo and could remarkably decrease the activity of acetylcholinesterase in mice brain. This study indicated that 7b could be considered as a potential multitarget agent against AD.

Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease.

A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Aß(1-42) aggregation, Cu(2+)-induced Aß(1-42) aggregation, human AChE-induced Aß(1-40) aggregation and disassembled Cu(2+)-induced aggregation of the well-structured Aß(1-42) fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study.