Discovery of novel deoxyvasicinone derivatives with benzenesulfonamide substituents as multifunctional agents against Alzheimer's disease.

A series of deoxyvasicinone derivatives with benzenesulfonamide substituents were designed and synthesized to find a multifunctional anti-Alzheimer's disease (AD) drug. The results of the biological activity evaluation indicated that most compounds demonstrated selective inhibition of acetylcholinesterase (AChE). Among them, g17 exhibited the most potent inhibitory effect on AChE (IC50 = 0.24 ± 0.04 µM). Additionally, g17 exhibited promising properties as a metal chelator and inhibitor of amyloid ß peptides self-aggregation (68.34 % ± 1.16 %). Research on oxidative stress has shown that g17 displays neuroprotective effects and effectively suppresses the intracellular accumulation of reactive oxygen species. Besides, g17 demonstrated remarkable anti-neuroinflammatory effects by significantly reducing the production of pro-inflammatory cytokines (such as NO, IL-1ß, and TNF-α) and inhibiting the expression of inflammatory mediators iNOS and COX-2. In vivo studies showed that g17 significantly improved AD model mice's cognitive and memory abilities. Histological examination of mouse hippocampal tissue sections using hematoxylin and eosin staining revealed that g17 effectively mitigates neuronal damage. Considering the multifunctional properties of g17, it is regarded as a promising lead compound for treating AD.

Design, synthesis, and biological evaluation of novel tryptanthrin derivatives as selective acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

Two novel series of tryptanthrin (TRYP) derivatives were designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Inhibition assay against cholinesterase (ChE) indicated that these derivatives can act as acetylcholinesterase (AChE) inhibitors with selectivity over butyrylcholinesterase (BuChE). Among them, n1 exhibited the most excellent ChE inhibitory potency (AChE, IC50 = 12.17 ± 1.50 nM; BuChE, IC50 = 6.29 ± 0.48 µΜ; selectivity index = 517). Molecular docking studies indicated that compound n1 can interact with amino acid residues in the catalytic active site and peripheral anionic site of AChE and the molecular dynamics (MD) simulation studies demonstrated that the AChE-n1 complex had good stability. N1 also exhibited anti-amyloid-ß (Aß) aggregation (63.48 % ± 1.02 %, 100 µΜ) and anti-neuroinflammation activity (NO, IL-1ß, TNF-α; IC50 = 2.13 ± 0.54 µΜ, 2.21 ± 0.37 µΜ, 2.47 ± 0.07 µΜ, respectively), and n1 had neuroprotective and metal-chelating properties. Further studies indicated n1 had proper blood-brain barrier permeability in the Parallel artificial membrane permeation assay. In vivo studies found that n1 effectively improved learning and memory impairment in scopolamine-induced AD mouse models. Nissl staining ofmice hippocampaltissue sections revealed that n1 restored neuronal cells in the hippocampus CA3 and CA1 regions. These findings suggested that n1 can be a promising compound for further development of multifunctional agents for AD treatment.

Discovery of novel TLR4/MD-2 inhibitors: Receptor structure-based virtual screening studies and anti-inflammatory evaluation.

In this study, a receptor structure-based virtual screening strategy was constructed using a computer-aided drug design. First, the compounds were filtered based on the Lipinski pentad and adsorption, distribution, metabolism, excretion, and toxicity profiles. Then, receptor structure-based pharmacophore models were constructed and screened. Finally, the in vitro toxicity and anti-inflammatory activities of hit compounds were initially evaluated to investigate their in vitro anti-inflammatory effects and mechanisms of action. The results revealed that hit 94 had the best anti-inflammatory activity and low toxicity while inhibiting the activation of Toll-like receptor (TLR) 4/myeloid differentiation factor 2 (MD2)-associated signaling pathways of nuclear factor-κB and mitogen-activated protein kinase. In vivo adjuvant arthritis results also revealed that hit 94 ameliorated foot swelling to a greater extent in rats compared with the positive control drug indomethacin. These results suggest that hit 94 can be used as a potential TLR/MD2 inhibitor for inflammatory diseases.

Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease.

Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 ± 0.04 µM) and butyrylcholinesterase (BuChE, IC50 = 6.11 ± 0.15 µM). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced Aß aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aß. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1ß, TNF-α; IC50 = 0.62 ± 0.07 µM, 1.78 ± 0.21 µM, 1.31 ± 0.28 µM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood-brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD.

Soybean WRINKLED1 protein GmWRI1a promotes flowering under long-day conditions via regulating expressions of flowering-related genes.

Flowering time is an important agronomic character that influences the adaptability and yield of soybean [Glycine max (L.) Merrill]. WRINKLED 1 (WRI1) plays an important regulatory role in plant growth and development. In this study, we found that the expression of GmWIR1a could be induced by long days. Compared with the wild type, transgenic soybean overexpressing GmWRI1a showed earlier flowering and maturity under long days but no significant changes under short days. Overexpression of GmWRI1a led to up-regulated expression of genes involved in the regulation of flowering time. The GmWRI1a protein was able to directly bind to the promoter regions of GmAP1, GmFUL1a, GmFUL2 and up-regulated their expression. GmCOL3 was identified by yeast one-hybrid library screening using the GmWRI1a promoter as bait. GmCOL3 was revealed to be a nucleus-localized protein that represses the transcription of GmWRI1a. Expression of GmCOL3 was induced by short days. Taken together, the results show that overexpression of GmWRI1a promotes flowering under long days by promoting the transcriptional activity of flowering-related genes in soybean, and that GmCOL3 binds to the GmWRI1a promoter and directly down-regulates its transcription. This discovery reveals a new function for GmWRI1a, which regulates flowering and maturity in soybean.

Novel tryptanthrin derivatives with benzenesulfonamide substituents: Design, synthesis, and anti-inflammatory evaluation.

Herein, two series of tryptanthrin derivatives with benzenesulfonamide substituents were designed and synthesized to discover novel anti-inflammatory agents. The anti-inflammatory activities of all derivatives were screened by evaluating their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. Among them, compound 8j exhibited the best NO inhibitory activity (IC50 = 1.25 ± 0.21 µM), with no obvious toxicity. Further evaluation showed that 8j could also significantly reduce the levels of pro-inflammatory cytokines interleukin-1ß (IL-1ß, IC50 = 8.48 ± 0.23 µM) and tumor necrosis factor-α (TNF-α, IC50 = 11.53 ± 0.35 µM) and downregulate the LPS-induced expression of iNOS and COX-2. Reverse docking of 8j suggested p38α as the molecular target, which is a well-known crucial player in the p38 MAPK signaling pathway that controls the transcription of pro-inflammatory mediators. Cellular thermal shift assay showed that 8j efficiently stabilized p38α in LPS-treated RAW264.7 cells. Western blot showed that inflammatory response was inhibited by 8j through inhibiting the phosphorylation of p38α and MK2 in the p38 MAPK signaling pathway. Finally, In vivo studies showed that 8j could significantly ameliorate the degree of foot swelling and knee joint pathology in adjuvant-induced arthritis (AIA) rats and reduce levels of TNF-α and IL-1ß in serum, achieving the effect of protecting synovial tissue and ameliorating arthritis. These findings suggested that 8j may be a promising compound for further development of anti-inflammatory agents.

Protective effects of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives to adjuvant-induced arthritis rats by regulating the NF-κB signaling pathway.

A series of (4-(1,2,4-oxadiazol-5-yl) phenyl)-2-aminoacetamide derivatives showed good anti-neuroinflammation in our previous study. Some studies have proven that the anti-inflammatory compounds effective for some specific diseases could also be used to treat other inflammatory diseases. In this study, the effects of these compounds on arthritis were further analyzed. First, in-vitro anti-inflammatory activity assessment indicated that these compounds have good anti-inflammatory activity. Among them, compound f15 showed the most prominent performance, it could significantly inhibit the production of relevant inflammatory factors in lipopolysaccharide (LPS)-induced RAW264.7 cells, with IC50 values of 1.55 ± 0.33, 3.83 ± 0.19, and 7.03 ± 0.24 µM against NO, IL-1ß, and TNF-α production, respectively. Preliminary mechanism studies indicated that f15 blocked the excitation of nuclear factor κB (NF-кB) signaling pathway in a concentration-dependent manner. Furthermore, in-vivo experiment showed that f15 reduced secondary foot swelling and arthritic index in adjuvant-induced arthritis (AIA) rats and inhibited the production of TNF-α and IL-1ß in serum. Histopathological analysis revealed that f15 alleviated inflammatory cell infiltration and synovial hyperplasia in rats with AIA. Thus, compound f15 could be considered to have the potential to be developed as a treatment for arthritis.

Novel quinoline-based derivatives: A new class of PDE4B inhibitors for adjuvant-induced arthritis.

A total of 31 quinoline-based derivatives were designed and synthesized to develop novel anti-inflammatory drugs. After the toxicity of synthetic compounds to RAW264.7 cells were evaluated in vitro, their anti-inflammatory activity was assessed by inhibiting lipopolysaccharide (LPS)-induced NO production levels in the RAW264.7 cells. Among the derivatives, compound f4 had the best anti-inflammatory activity, which could reduce the production of pro-inflammatory cytokines NO, IL-1ß, and TNF-α with corresponding IC50 values of 20.40 ± 0.94, 18.98 ± 0.21 and 23.48 ± 0.46 µM. Western blot showed that f4 could inhibit the expression of LPS-induced inflammatory mediators iNOS and COX-2. Molecular docking showed that f4 could also enter the PDE4B receptor binding pocket, and the cellular thermal shift assay method indicated that the PDE4B protein bound to f4 had increased stability. Meanwhile, the inhibitory effect of this compound on the PDE4B enzyme (IC50 = 0.94 ± 0.36 µM) was comparable to that of the positive drug rolipram (IC50 = 1.04 ± 0.28 µM). Finally, in vivo studies showed that f4 could improve the degree of foot swelling and knee joint pathology in adjuvant-induced arthritic rats and decrease the levels of serum inflammatory factors TNF-α and IL-1ß in a dose-dependent manner. Therefore, the development and design of quinoline-based derivatives for anti-inflammatory applications could be considered opportunities and challenges.

Design, synthesis, and biological evaluation of novel (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.

On the basis of our previous work, a novel series of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives were synthesized and evaluated as multifunctional ligands for the treatment of Alzheimer's disease (AD). Biological evaluations indicated that the derivatives can be used as anti-AD drugs that have multifunctional properties, inhibit the activity of butyrylcholinesterase (BuChE), inhibit neuroinflammation, have neuroprotective properties, and inhibit the self-aggregation of Aß. Compound f9 showed good potency in BuChE inhibition (IC50: 1.28 ± 0.18 µM), anti-neuroinflammatory potency (NO, IL-1ß, TNF-α; IC50: 0.67 ± 0.14, 1.61 ± 0.21, 4.15 ± 0.44 µM, respectively), and inhibited of Aß self-aggregation (51.91 ± 3.90%). Preliminary anti-inflammatory mechanism studies indicated that the representative compound f9 blocked the activation of the NF-κB signaling pathway. Moreover, f9 exhibited 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect, and an inhibitory effect on the production of intracellular reactive oxygen species (ROS). In the bi-directional transport assay, f9 displayed proper blood-brain barrier (BBB) permeability. In addition, the title compound improved memory and cognitive functions in a mouse model induced by scopolamine. Hence, the compound f9 can be considered as a promising lead compound for further investigation in the treatment of AD.

Synthesis and evaluation of the anti-inflammatory activity of novel 8-quinolinesulfonamide derivatives as TLR4/MD-2 inhibitors with efficacy in adjuvant-induced arthritis.

In this study, a series of 8-quinolinesulfonamidederivatives was synthesized, and their anti-inflammatory activity was evaluated. Among them, compound 3l was found to be the best anti-inflammatory agent, with IC50 values of 2.61 ± 0.39, 9.74 ± 0.85, and 12.71 ± 1.34 µM against NO, TNF-α and IL-1ß production respectively. And 3l could significantly prevent lipopolysaccharide (LPS)-induced expression of inflammatory mediators (iNOS and COX-2). Molecule docking results showed that 3l could bind to the LPS binding site of toll-like receptor 4 (TLR4)/MD-2, and 3l was then identified as TLR4/MD-2 inhibitor by co-immunoprecipitation (co-IP) and cellular thermal shift assay (CTESA). Preliminary mechanism studies indicated that 3l could prevent TLR4 from being activated by disrupting TLR4/MD-2 heterodimerization and TLR4 homodimerization, thereby blocking the activation of the NF-κB/MAPK signaling pathway. Furthermore, observation of rat foot swelling, joint pathology and serum inflammatory cytokine levels proved that compound 3l had a significant therapeutic effect on adjuvant-induced arthritis (AIA) in rats in vivo. These results indicated that compound 3l is a potential anti-inflammatory agent, from which more effective anti-inflammatory drugs could be developed.

Soluble metal ions migration and distribution in sludge electro-dewatering.

In this study, the effects of electro-dewatering technology applied to high-salt industrial sludge dewatering performance were investigated, in terms of ions migrations and distributions by model simulation and layered tests. The simulation results of Na+ and K+ migrations were consistent with layered experiments during electro-dewatering, where Na+ ions migrated faster than K+ ions. More than 80% Na+ ions were removed by electromigration, which would be useful in subsequent sludge utilization. The mass specific energy consumption was reduced from 350.08 to 295.88 kWh per ton sludge by means of piecewise voltage electro-dewatering method. This study provided insights into the soluble ions migration and distribution mechanism in electro-dewatering process, and a method to improve commercial application performance of high-salt industrial sludge electro-dewatering.