Dual functional antioxidant and butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of novel melatonin-alkylbenzylamine hybrids.

Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (huBuChE IC50 = 1.20 µM, huAChE IC50 = 177.49 µM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for huBuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs.

A multi-target directed ligands strategy for the treatment of Alzheimer's disease: Dimethyl fumarate plus Tranilast modified Dithiocarbate as AChE inhibitor and Nrf2 activator.

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c2 displayed the mighty inhibitory activity to hAChE (IC50 = 0.053 µM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c2 bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c2 as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c2 rescued BV-2 cells from H2O2-induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c2, we observed that 4c2 could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c2 was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c2 was a promising multi-targeted agent for treating AD.

Design, Synthesis and Anti-Tumor Activity Evaluation of Novel 3,4-(Methylenedioxy)cinnamic Acid Amide-Dithiocarbamate Derivatives.

The fragments, 3,4-(methylenedioxy)cinnamic acid amide and dithiocarbamates, have received increasing attention because of their multiple pharmacological activities in recent years, especially in anti-tumor. We synthesized 17 novel 3,4-(methylenedioxy)cinnamic acid amide-dithiocarbamate derivatives based on the principle of pharmacophore assembly and discovered that compound 4a7 displayed the most potent antiproliferative activity against HeLa cells with IC50 value of 1.01 µM. Further mechanistic studies revealed that 4a7 triggered apoptosis in HeLa cells via activating mitochondria-mediated intrinsic pathways and effectively inhibited colony formation. Also, 4a7 had the ability to arrest cell cycle in the G2/M phase as well as to inhibit the migration in HeLa cells. More importantly, acute toxicity experiments showed that 4a7 had good safety in vivo. All the results suggested that compound 4a7 might serve as a promising lead compound that merited further attention in future anti-tumor drug discovery.

Vanadium compounds induced damage of human umbilical vein endothelial cells and the protective effect of berberine.

This study was conducted to investigate the damage caused by vanadium compounds and to explore the protective effects of berberine (BBR) in human umbilical vein endothelial cells (HUVECs). BBR is a biologically active small molecule found in Coptis rhizome, a remedy used in traditional Chinese medicine to treat diabetes. BBR has also been shown to lower blood glucose in diabetic patients. MTT assay was performed to observe the influence of bis(acetylacetonato)-oxidovanadium [VO(acac)2] or sodium metavanadate (NaVO3) and BBR on viability of HUVECs. The monolayer permeability of the HUVECs was assessed by measuring the transendothelial electrical resistance (TER). The endothelial nitric oxide synthase (eNOS) activity was detected by ELISA. Flow cytometry was performed to detect the generation of reactive oxygen species (ROS). The results showed that the viability of HUVECs was decreased by treatment with vanadium compounds 50-400 µM in a concentration-dependent manner, while 0.01-1 µM BBR effectively protected HUVECs from the inhibitory effects of vanadium compounds on cell viability. Also 100 and 200 µM VO(acac)2 induced high permeability and decreased eNOS activity in HUVECs. While 0.01-1 µM BBR showed no improvement in the permeability, and failed to reverse the VO(acac)2-induced changes of eNOS activity, but BBR treatment increased the eNOS activity in control cells. The addition of 200 µM VO(acac)2 significantly induced ROS generation in HUVECs, while 0.01 or 0.1 µM BBR reversed the change of ROS. In summary, BBR has protective effects in HUVECs damage induced by vanadium compounds, which is not mediated by eNOS, but related to reduced intracellular ROS.