The structural modification and biological evaluation of tetrahydrothienopyridine derivatives as selective BChE inhibitors.

A series of tetrahydrothienopyridine derivatives have been designed, synthesized, and evaluated as selective BChE inhibitors. Compounds were analyzed via HRMS, 1H NMR, and 13C NMR. The inhibitory effects were evaluated according to the method of Ellman et al. 6n was the most potent and selective inhibitor against BChE (eeAChE IC50 = 686.4 ± 478.6 µM, eqBChE IC50 = 10.5 ± 5.0 nM, SI = 6.5*104, hBChE IC50 = 32.5 ± 6.5 nM). Cell-based assays have confirmed the low neurotoxicity of 6a and 6n and their moderate neuroprotective effects. Compounds 6a and 6n provide novel chemical entities for the treatment of Alzheimer's disease.

Chemical profiling and identification of Radix Cudramiae and their metabolites in rats using an ultra-high-performance liquid chromatography method coupled with time-of-flight tandem mass spectrometry.

Radix Cudramiae, known as "Chuan-Po-Shi" in China, is a herbal medicine widely used in the southwest of the country, especially applied by the Miao and Zhuang nationalities for the treatment of liver diseases, such as acute liver injury and liver fibrosis. As a kind of ethnomedicine, the report on its chemical analysis was still blank, which restricted its clinical application. Therefore, this paper aimed to illustrate the chemical characteristics of Radix Cudramiae. A rapid analytical strategy based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was developed to profile the natural small-molecular compounds in Radix Cudramiae, as well as the related prototypes and their metabolites in rats after drug administration. As a result, a total of 74 compounds were detected in the aqueous exact of Radix Cudramiae. In vivo, 45 chemicals including 16 prototypes and 29 metabolites in rat serum, along with 35 chemicals including 17 prototypes and 18 metabolites in rat liver, were screened out and identified. For the first time, the chemical constituents of Radix Cudramiae and their metabolic characteristics were discovered. It was hoped that this work would be beneficial for the safe and effective application of Radix Cudramiae in a clinic.

Efficient Synthesis and In Vitro Hypoglycemic Activity of Rare Apigenin Glycosylation Derivatives.

Apigenin is a natural flavonoid with significant biological activity, but poor solubility in water and low bioavailability limits its use in the food and pharmaceutical industries. In this paper, apigenin-7-O-ß-(6″-O)-d-glucoside (AG) and apigenin-7-O-ß-(6″-O-succinyl)-d-glucoside (SAG), rare apigenin glycosyl and succinyl derivatives formed by the organic solvent-tolerant bacteria Bacillus licheniformis WNJ02 were used in a 10.0% DMSO (v/v) system. The water solubility of SAG was 174 times that of apigenin, which solved the application problem. In the biotransformation reaction, the conversion rate of apigenin (1.0 g/L) was 100% at 24 h, and the yield of SAG was 94.2%. Molecular docking showed that the hypoglycemic activity of apigenin, apigenin-7-glucosides (AG), and SAG was mediated by binding with amino acids of α-glucosidase. The molecular docking results were verified by an in vitro anti-α-glucosidase assay and glucose consumption assay of active compounds. SAG had significant anti-α-glucosidase activity, with an IC50 of 0.485 mM and enhanced glucose consumption in HepG2 cells, which make it an excellent α-glucosidase inhibitor.

HuoXueTongFu Formula Alleviates Intraperitoneal Adhesion by Regulating Macrophage Polarization and the SOCS/JAK2/STAT/PPAR-γ Signalling Pathway.

Intraperitoneal adhesion is a common complication after abdominal surgery, which seriously affects the quality of life of patients. HuoXueTongFu Formula (HXTF) plays an important role in the prevention and treatment of intraperitoneal adhesions. However, the molecular-related mechanisms are still not fully known. In this study, the model of Intrapetitoneal adhesion was established by cecum abrasion and treated with HXTF for one week. RAW264.7 cells were given LPS, IFN-γ, IL-4, HXTF-medicated serum, and PPAR-γ agonist/antagonist, respectively. Histopathology, flow cytometry, ELISA, real-time PCR, and Western blotting were used to further detect the related protein, M1/M2 polarization tendency, and PPAR-γ nuclear translocation. The deposition of collagen fibres reduced in the local area of rats after the operation with HXTF treatment. Similar to IL-4, HXTF induced a tendency for macrophages to polarize toward M2 and promoted peroxisome proliferator-activated receptor-gamma (PPAR-γ) nuclear translocation. Furthermore, the use of HXTF and PPAR-γ agonists downregulated macrophage M1 polarization-related factors IL-1, IL-6, and TNF-alpha and upregulated M2 polarization-related factors IL-4, IL-10, and TGF-beta 1. Meanwhile, the use of HXTF and PPAR-γ agonists downregulated the SOCS3/JAK2/STAT1 pathway and activated the SOCS1/STAT6/PPAR-γ pathway. These results show that HXTF may reduce intraperitoneal adhesion by inducing macrophage M2 polarization and regulating the SOCS/JAK2/STAT/PPAR-γ pathway.

Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid ß-protein self-aggregation by 65.49% at 25 µM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid ß-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC50 = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.

Comparative pharmacokinetic study of pyranocoumarins and khellactone in normal and acute lung injury rats after oral administration of Peucedanum praeruptorum Dunn extracts using a rapid and sensitive liquid chromatography-tandem mass spectrometry method.

Pyranocoumarins are the main constitutes in Peucedanum praeruptorum Dunn and possess various biological activities. In this article, we developed and validated a rapid and sensitive liquid chromatography-tandem mass spectrometry method for the targeted quantification of the pyranocoumarins, praeruptorin A, praeruptorin B and praeruptorin E, and khellactone, which is a common metabolite of these pyranocoumarins in rat plasma samples. We then performed a comparative pharmacokinetic study of these pyranocoumarins and khellactone in normal and lipopolysaccharide-induced acute lung injury (ALI) in rats following oral administration of P. praeruptorum Dunn extracts. Calibration curves gave desirable linearity (r > 0.99) and the lower limit of quantifications were sufficient for quantitative analysis. The precision and accuracy were assessed by intra-batch and inter-batch assays, and the relative standard deviations were all within 10.23% and the accuracy (relative error) was between -5.52% and 8.68%. The extraction recoveries, matrix effects and stability were also acceptable. The pharmacokinetic study revealed that the area under the concentration-time curve (0-t) of khellactone in ALI rats was significantly decreased compared with the normal rats. Meanwhile, the systemic exposures of these pyranocoumarins were slightly higher in the ALI rats than those in normal rats were. The pharmacokinetic study in the pathological state might provide information that was more comprehensive to guide the clinical usage of P. praeruptorum Dunn.

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer's Disease.

For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 µM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 µM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aß1-42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.

Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.

The Design and Optimization of Monomeric Multitarget Peptides for the Treatment of Multifactorial Diseases.

Compared with single-target drugs, multitarget drugs may improve the safety and efficacy of the treatment of multifactorial diseases. However, few multitarget drugs are on the market or in clinical trials currently, and multitarget small molecules account for the majority. Compared with multitarget small molecules, multitarget peptides have unique advantages and show good effects in a variety of diseases. This article discusses the design process of multitarget peptides in four aspects, including target combination, peptide selection, lead generation, and lead optimization. In addition, we analyzed in detail the research cases of multitarget peptides for several multifactorial diseases over years, aiming to reveal the trends and insights of the potential uses of multitarget peptides.

Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010-2020).

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is characterized by the primary risk factor, age. Several attempts have been made to treat AD, while most of them end in failure. However, with the deepening study of pathogenesis of AD, the expression of HDAC6 in the hippocampus, which plays a major role of the memory formation, is becoming worth of notice. Neurofibrillary tangles (NFTs), a remarkable lesion in AD, has been characterized in association with the abnormal accumulation of hyperphosphorylated Tau, which is mainly caused by the high expression of HDAC6. On the other hand, the hypoacetylated tubulin induced by HDAC6 is also fatal for the neuronal transport, which is the key impact of the formation of axons and dendrites. Overall, the significantly increased expression of HDAC6 in brain regions is deleterious to neuron survival in AD patients. Based on the above research, the inhibition of HDAC6 seems to be a potential therapeutic method for the treatment of AD. Up to now, various types of HDAC6 inhibitors have been discovered. This review mainly analyzes the HDAC6 inhibitors reported amid 2010-2020 in terms of their structure, selectivity and pharmacological impact towards AD. And we aim at facilitating the design and development of better HDAC6 inhibitors in the future.

Identification of 4-aminoquinoline core for the design of new cholinesterase inhibitors.

Inhibition of acetylcholinesterase (AChE) using small molecules is still one of the most successful therapeutic strategies in the treatment of Alzheimer's disease (AD). Previously we reported compound T5369186 with a core of quinolone as a new cholinesterase inhibitor. In the present study, in order to identify new cores for the designing of AChE inhibitors, we screened different derivatives of this core with the aim to identify the best core as the starting point for further optimization. Based on the results, we confirmed that only 4-aminoquinoline (compound 04 and 07) had cholinesterase inhibitory effects. Considering the simple structure and high inhibitory potency against AChE, 4-aminoquinoline provides a good starting core for further designing novel multifunctional AChEIs.