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In this study, indolyl-1,2,4-oxidizable derivatives were synthesized and in vitro evaluated as new class of non-competitive α-glucosidase inhibitors. Most of the compounds showed better inhibitory activity than reference drug (acarbose), with compound 35 being the most potent inhibitor. Kinetic analysis indicated that compound 35 had non-competitive inhibition on α-glucosidase, and fluorescence quenching experiment confirmed the direct binding of 35 to α-glucosidase. Besides, some selected compounds had no effect on cell viability of human normal hepatocyte (LO2) and human liver cancer (HepG2) cells. Thus, this work provides a new chemotype for developing novel drugs against type 2 diabetes. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3β (GSK-3β) is a highly conserved multifunctional serine/threonine (Ser/Thr) protein kinase widely expressed in many tissues. GSK-3β inhibitors could be used in the treatment of human key diseases, such as cancer, Alzheimer's disease, Parkinson's disease, inflammation, type-II diabetes, and so on, due to the multi-role of GSK-3β in the hepatic glycolysis regulation, cell signaling pathways, and phosphorylation of various proteins. Recently, sets of diverse GSK-3β inhibitors have been prepared, and biologically evaluated in vitro and in vivo in different screening models. This review summarizes the latest developments in GSK-3β inhibitors unclosed from 2015 to 2019, including their structure–activity relationship and bioactivity studies. [ABSTRACT FROM AUTHOR]

Cysteine (Cys) is an important endogenous amino acid and plays critical physiological roles in living systems. Herein, an endoplasmic reticulum (ER)-targeting fluorescent probe (FER-Cys) was designed and prepared for imaging of Cys in living cells. The probe FER-Cys consists of a fluorescein framework as the fluorescent platform, acrylate group as the response site for the selective recognition of Cys, and ER-specific p-toluenesulfonamide fragment. After the response of probe FER-Cys to Cys, a turn-on fluorescence signal at 546 nm could be detected obviously. The probe FER-Cys further shows desirable selectivity to Cys. Finally, the probe FER-Cys was proven to selectively detect Cys in live cells and successfully image the changes of Cys level in the cell models of H2O2-induced redox imbalance. [ABSTRACT FROM AUTHOR]

The objective of the current study is to evaluate the potency of quinoline/cinnamic acid hybrids against amyloid-beta (Aβ) aggregation. In total, six new target quinoline/cinnamic acid hybrids were synthesized and screened for their in vitro anti-Aβ42 aggregation activity. Some hybrids, including (E)-N-(2-cinnamamidoethyl)-6,7-dimethoxyquinoline-2-carboxamide, (E)-6,7-dimethoxy-N-[2-[3-(4-methoxyphenyl)acrylamido]ethyl]quinoline-2-carboxamide, and (E)-6,7-dimethoxy-N-[2-[3-(2-methoxyphenyl)acrylamido]ethyl]quinoline-2-carboxamide, showed significant anti-Aβ42 aggregation activity. Molecular docking method was used to predict the binding modes of these compounds with Aβ42. In addition, their cytotoxicity towards neuroblastoma SH-SY5Y and human normal hepatocyte LO2 cells were tested. Neuroprotective evaluation demonstrated that these compounds could attenuate Aβ42-induced neurotoxicity towards SH-SY5Y cells in a dose-dependent manner. Overall, the present study provides quinoline/cinnamic acid hybrids as a new template for developing Aβ aggregation inhibitors against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Although the mechanism of Alzheimer's disease (AD) is still not fully understood, the development of multifunctional AChE inhibitors remains a research focus for AD treatment. In this study, 48 AChE candidate inhibitors were picked out from SPECS database through a pharmacophore- and molecular docking-based virtual screening. The biological evaluation results indicated that four compounds 7, 29, 41 and 48 with different scaffolds exhibited potent and selective AChE inhibitory activity, with the best IC50 value of 1.62 ± 0.11 μM obtained for 48. Then their mechanism of action, the inhibition on Aβ aggregation, neurotoxicity, and neuroprotective activity against Aβ-induced nerve cell injury were well studied. The binding mode of 48 with AChE was also proposed. The present bioassay results indicated that these multifunctional AChE inhibitors were worth for further structural derivatization to make them the anti-AD lead compounds. [ABSTRACT FROM AUTHOR]

Abstract: A series of new 2-(3-aminophenyl)-benzothiazole derivatives were synthesized and evaluated for their in vitro antiproliferative activity against various human cancer cell lines including A549, HeLa, HepG2, MCF-7, MV4-11, and DB. Among the tested compounds, N-[3-(benzo[d]thiazol-2-yl)phenyl]nicotinamide displayed significantly improved antiproliferative activity toward A549 and MV4-11 cells with IC50 values of 5.42 ± 1.33 and 7.51 ± 0.98 μM, respectively, much stronger than the hit 3-(benzo[d]thiazol-2-yl)-N-(4-bromobenzyl)aniline. Furthermore, flow cytometric analysis indicated that N-[3-(benzo[d]thiazol-2-yl)phenyl]nicotinamide induced A549 cell apoptosis with cell cycle arrest at G1 phase in a concentration-dependent manner.Graphical abstract: [ABSTRACT FROM AUTHOR]

A series of new coumarin/piperazine hybrids were synthesized and evaluated for anticholinesterase activity. Among them, compounds 4d and 4t exhibited potent human acetylcholinesterase (hAChE) inhibitory activity with IC50 values of 2.42 and 9.89 μM, respectively, and 4t displayed highest selectivity toward hAChE over human butyrylcholinesterase (hBChE) by 9.8-fold. In addition, both compounds did not show observed cytotoxicity against SH-SY5Y neuroblastoma cell line at 100 μM. Kinetic analysis in tandem with molecular docking study revealed that these hybrids targeted both catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. The preliminary results highlighted 4t as an anti-Alzheimer’s disease lead compound worthy of further investigation. [ABSTRACT FROM AUTHOR]

A series of new benzothiazol-based 1,3,4-oxadiazole derivatives were synthesized and evaluated for their neuroprotective effects against Aβ-induced toxicity in SH-SY5Y cells. The bioassay results indicated that most of the tested compounds exhibited promising neuroprotective activity. In particular, compound 2-[[[5-[(4-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole showed the most potent activity (95.7% of cell viability at 10 μM), better than the positive control EGCG (90.7% of cell viability at 10 μM). Furthermore, compounds 2-[[[5-[(2-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, 2-[[[5-[(4-bromo-2-fluorophenylmethylyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, and 2-[[[5-[(4-methoxyphenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole displayed neuroprotective activity similar to EGCG (87.7, 89.1, and 87.7% of cell viability, respectively, at 10 μM). The preliminary SARs analysis indicated that benzene ring is the key factor for the neuroprotective activity and the bromo atom substituted at 4-position of the benzene ring favors the neuroprotective activity. In addition, the fluoro group in the benzene ring appears not beneficial for the neuroprotective activity. Graphical abstract: [ABSTRACT FROM AUTHOR]

Macrolides, which comprise a family of lactones with different ring sizes, belong to the polyketide class of natural products. Resorcinolic macrolides, an important subgroup, possess interesting structures and exhibit a wide variety of bioactivities, such as anti-tumor, anti-bacteria, and anti-malaria activities, etc. This review summarizes progress in isolation, bioactivity studies, biosynthesis, and representative chemical syntheses of this group of macrolides in recent decades, encompassing 63 naturally occurring macrolides published in 120 articles. [ABSTRACT FROM AUTHOR]

Aim:des-O-methyllasiodiplodin (DML) from Cerbera manghas has shown antagonistic activity against mineralocorticoid receptor (MR). Considering the involvement of MR in the insulin tolerance, we attempted to investigate the potential of DML in the treatment of type 2 diabetes mellitus (T2DM).Methods:Surface plasmon resonance (SPR) technology and reporter gene-based assays were used to study protein-small molecule interactions. HepG2 and 3T3-L1 cells were treated with H2O2 (0.2 mmol/L) or aldosterone (10 nmol/L) for 24 h. The expression of MR in the cells was downregulated with siRNA. The anti-inflammatory effect of the compound was evaluated, respectively. db/db mice were administered DML (30 mg·kg−1·d−1) for 4 weeks. Serum biochemical parameters and insulin sensitivity were examined. The expression levels of pro-inflammatory cytokines (MCP-1, TNF-α and IL-6) and ROS-related genes (NADPH p47 subunit and transcriptional factor PU.1) in adipose tissues and livers were analyzed using real-time RT-PCR.Results:In HepG2 and 3T3-L1 cells, both H2O2 and aldosterone markedly stimulates the expression of MCP-1, TNFα, IL-6, p47 and PU.1 genes. Co-treatment with DML (10 μmol/L) significantly reduced the H2O2- or aldosterone-induced expression of these genes. SPR-based assay confirmed the antagonistic activity of DML against the interaction between SRC-1 and MR-LBD. Furthermore, DML decreased aldosterone-induced MR transcriptional activity in a dose-dependent manner. Downregulation of MR with siRNA in the cells prevented or significantly attenuated aldosterone-stimulated expression of these genes, whereas DML did no longer affect the expression of these genes except that of IL-6. Oral administration of DML effectively reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) in db/db mice. The treatment also rectified the expression of pro-inflammatory factor and ROS-related genes in db/db mice.Conclusion:DML effectively lowers the blood glucose level in db/db mice possibly via ameliorating the expression of obesity-related pro-inflammatory cytokines, highlighting the potential of the marine natural product as a drug lead for the treatment of metabolic disorders. [ABSTRACT FROM AUTHOR]

This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented. [ABSTRACT FROM AUTHOR]