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ABSTRACT The synthesis and structural analysis of complexes derived from (E)‐N′‐(3,5‐di‐tert‐butyl‐2‐hydroxybenzylidene) isonicotino hydrazide (ITB ligand) were examined using multiple analytical techniques. These techniques included TGA, decomposition point determination, elemental analysis (CHN), spectroscopic (IR, NMR, mass spectrometry) analysis, magnetic susceptibility, conductivity, as well UV–Vis spectrum analysis, along with theoretical studies. Molar conductance values indicated that the Cd (II), Co (II), Cu (II), Ni (II), and Zn (II) complexes are non‐electrolytes in fresh DMSO solutions, with conductance values ranging from 8.5 to 14.35 Ω−1 cm2 mol−1. IR spectra suggested which the ligand coordinates through the metal ions in a tridentate fashion, utilizing the (N & O) donor sites from the (CN & CO & CO) groups in the hydroxybenzylidene moiety. Analytical data from solution complexation, job's method suggested a 1:1 (metal:ligand) molar ratio. The stability order of the complexes was determined as ITBCo > ITBCu > ITBNi > ITBZn > ITBCd, consistent with the stability constant (Kf) values. The pH profile indicated that the studied complexes exhibit stability upon a wide pH scale, typically between (pH = 4:10). Magnetic and electronic spectral analyses helped deduce the ligand coordination abilities and the geometric structures of the complexes. In vitro (antimicrobial & anticancer) performances of the studied complexes were tested versus various (microbial strains & cancer cell lines), revealing higher activity in the chelates assessed to the free (ITB) ligand. The antioxidant potential was also assessed using the DPPH assay. Finally, molecular docking was performed toward estimate the binding efficiency between various protein receptors and the compounds, with results aligning with the biological investigations. [ABSTRACT FROM AUTHOR]

The history of effective anti-cancer medications begins with the discovery of cisplatin's anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl}2(μ-bridging ligand)]2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy. [ABSTRACT FROM AUTHOR]

A simple and rapid procedure is developed for the synthesis of 5-arylidene-thiazolidine-2,4-dione derivatives by the Knoevenagel reaction between a variety of aromatic aldehydes and thiazolidine-2,4-dione, catalyzed by N,N-dimethylaminopyridine. The reactions were carried out without solvent giving excellent yields of the expected products. The antioxidant activity of all the molecules prepared was evaluated and two of them gave encouraging results. In addition, an extensive theoretical study was carried out such as density functional theory (DFT) calculations, theoretical predictions of biological activities and molecular docking. [ABSTRACT FROM AUTHOR]

BRAF is the most common serine-threonine protein kinase and regulates signal transduction from RAS to MEK inside the cell. The BRAF is a highly active isoform of RAF kinase. BRAF has two domains such as regulatory and kinase domains. The BRAF inhibitors bind in the c-terminus of the kinase domain and inhibit the downstream pathways. The mutation occurs mainly in the A-loop of the kinase domain. The mutation occurs due to a conversion of valine to glutamate/lysine/arginine/aspartic acid at 600th position. Among the diverse mutations, BRAFV600E is the most common and responsible for numerous cancer such as melanoma, colorectal, ovarian, and thyroid cancer. Due to mutations in RAC1, loss of PTEN, NF1, CCND1, USP28-FBW7 complex, COT overexpression, and CCND1 amplification, the BRAF kinase enzyme developed resistance over the commercially available BRAF inhibitors. There is still unmute urgence for the development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In the current study, we described the structure, activation, downstream signaling pathway, and mutation of BRAF. Our group also provided a detailed review of BRAF inhibitors from the last five years (2018–2023) highlighting the structure–activity relationship, mechanistic study, and molecular docking studies. We hope that the current analysis will be a useful resource for researchers and provide chemists a glimpse into the future as design and development of more effective and secure BRAF kinase inhibitors. The development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In depth description about different heterocyclic scaffolds (quinoline, imidazole, pyridine, triazole, pyrrole etc.) as BRAF inhibitors from the last five years (2018–2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies. [ABSTRACT FROM AUTHOR]

In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV‐1) inhibitors with improved drug resistance profiles and favorable drug‐like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non‐nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano‐substituted benzyl moiety proved to be the most effective inhibitor against HIV‐1 wild‐type and mutant strains (EC50 = 0.0039–0.338 μM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 μM). Preliminary structure–activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug‐likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half‐lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti‐HIV‐1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug‐like profiles. [ABSTRACT FROM AUTHOR]

In this study, a novel terpolymer was successfully obtained via the polycondensation polymerization of p-phenylenediamine and 2-aminothiazole with formaldehyde, employing dimethylformamide as a catalyst. The molar ratio of 1:1:2 for the reacting monomers yielded the newly devised p-phenylenediamine-2-aminothiazole-formaldehyde (P2ATF) terpolymer. Subsequently, the terpolymer was utilized as a ligand to form a copper complex by combining it with Cu2+ ions. To check the structure of both the terpolymer and its copper complex, a comprehensive array of techniques like Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, nuclear magnetic resonance, and elemental analysis were employed. Gel permeation chromatography was employed to determine the average terpolymer molecular weight. The surface characteristics of the terpolymer and its metal complex were investigated using scanning electron microscopy, providing insights into their morphology. Furthermore, the thermal properties of the terpolymer and its metal complex were examined using thermogravimetric analysis, allowing for an assessment of their thermal breakdown behavior. They also were subjected to biological evaluations against a diverse range of microorganisms, encompassing Escherichia coli, Staphylococcus aureus, Candida albicans, and Aspergillus niger. The findings from these assessments provide valuable insights into the potential biological activities of both the ligand and its complex, enhancing our understanding of their potential applications. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the top ten causes of death worldwide, accounting for 6.7 million deaths in 2021, and is one of the most rapidly growing global health emergencies of this century. Although several classes of therapeutic drugs have been invented and applied in clinical practice, diabetes continues to pose a serious and growing threat to public health and places a tremendous burden on those affected and their families. The strategy of reducing carbohydrate digestibility by inhibiting the activities of α-glucosidase and α-amylase is regarded as a promising preventative treatment for type 2 diabetes. In this study, we investigated the dual inhibitory effect against two polysaccharide hydrolytic enzymes of flavonoid derivatives from an in-house chemical database. By combining molecular docking and structure–activity relationship analysis, twelve compounds with docking energies less than or equal to − 8.0 kcal mol−1 and containing required structural features for dual inhibition of the two enzymes were identified and subjected to chemical synthesis and in vitro evaluation. The obtained results showed that five compounds exhibited dual inhibitory effects on the target enzymes with better IC50 values than the approved positive control acarbose. Molecular dynamics simulations were performed to elucidate the binding of these flavonoids to the enzymes. The predicted pharmacokinetic and toxicological properties suggest that these compounds are viable for further development as type 2 diabetes drugs. [ABSTRACT FROM AUTHOR]

This study used micro-analyses, (FTIR, UV-Vis) spectra, magnetic, thermogravimetric, X-ray powder diffraction (XRD) patterns, and transmittance electron microscopy (TEM) techniques to characterize three synthesized theophylline (TPH) complexes with ruthenium(III), platinum(IV), and iridium(III) metal ions. The metal ions indicated above were found to align with the TPH drug chelate as a mono-dentate ligand via the deprotonated NH group at the nitrogen atom position N7, as verified by FTIR measurements. Additionally, the complexes conductivity and magnetic susceptibility were examined. The octahedral geometry for the synthesized complexes was proposed by the current data. Except for the iridium(III) complex, which has a non-electrolytic nature due to the presence of a chlorine atom inside the chelation sphere, the molar conductivity of the complexes in DMSO solution was electrolyte in nature. Theophylline complexes with a (metal: ligand) stoichiometry of 1:2 were produced. The TPH complexes have also been tested in vitro against G(+) bacteria (Bacillus subtilis and Staphylococcus Aureus) and G(-) bacteria (Pseudomonas aeruginosa and Escherichia coli) to evaluate their antibacterial efficacy. Human breast and liver cancer cell lines were used as a test for the TPH complexes in vitro anti-cancer properties. [ABSTRACT FROM AUTHOR]

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1,2, and 4 μM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6- dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression. [ABSTRACT FROM AUTHOR]

In this study, choline chloride/urea was used as a green deep eutectic solvent in the three-component reaction of hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrazole derivatives, and in the four-component reaction of methyl/ethyl acetoacetate, hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrano[2,3-c]pyrazole derivatives. Elemental analysis, ¹H, and 13C NMR spectroscopy were used to confirm the structure of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives. The antimicrobial effects of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives were investigated. In antimicrobial tests, instructions from clinical and laboratory standards institutes were used. Antimicrobial study was done on pathogenic gram-positive and gram-negative species, and specialized aquatic strains and fungal species. Using choline chloride/urea, novel pyrazole derivatives and pyrano[2,3-c]pyrazole derivatives were synthesized, and other derivatives were synthesized with higher efficiency in less time than some previously reported methods. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) obtained for derivatives were higher than some antibiotic drugs. Synthesis and reports of new derivatives of pyrazole and pyrano[2,3-c]pyrazole, and investigation and reports of their antimicrobial properties on gram-positive, gram-negative, and specialized aquatic and fungal species are among the novel and important findings of this study. [ABSTRACT FROM AUTHOR]

A functional compound selenium-enriched plant solid beverage was successfully developed by taking the selenium-enriched medicinal and edible plants Brassica oleracea, Pueraria lobata, Ampelopsis grossedentata, Polygonatum sibiricum, Chaenomeles sinensis, and tomato as the materials. At the meantime, its biological activities including antiproliferative, antioxidant, and analgesic activities were evaluated. The total selenium content of the compound solid beverage was determined by fluorescence spectrophotometry as 540±30.12 μg/kg. The biological results showed that the compound selenium-enriched plant solid beverage inhibited the proliferation of four cancerous cell lines A549, SMMC-7721, MCF-7, and SW480 with the inhibition values of 4.09%±1.36%, 19.48%±3.18%, 30.75%±1.45%, and 18.20%±1.12%, respectively, and had no cytotoxicity to the human normal lung epithelial cell BEAS-2B at a concentration of 100 μg/mL, indicating its antiproliferative effect against cancer cells in vitro. The compound solid beverage had a clearance ability of DPPH radical at a concentration-dependent manner with an IC50 value of 435.6±27.2 μg/mL. The compound solid beverage reduced the H2O2-induced oxidative damage and the intracellular reactive oxygen fluorescence intensity in LO2 cells, and presented a dose-effect relationship within a concentration of 5~20 μg/mL, revealing its obvious antioxidant activity (P

The history of effective anti-cancer medications begins with the discovery of cisplatin’s anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl}2(μ-bridging ligand)]2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.

Novel antimycobacterial compounds are needed to expand the existing toolbox of therapeutic agents, which sometimes fail to be effective. In our study we extracted, filtered, and aggregated the diverse data on antimycobacterial activity of chemical compounds from the ChEMBL database version 24.1. These training sets were used to create the classification and regression models with PASS and GUSAR software. The IOC chemical library consisting of approximately 200,000 chemical compounds was screened using these (Q)SAR models to select novel compounds potentially having antimycobacterial activity. The QikProp tool (Schrödinger) was used to predict ADME properties and find compounds with acceptable ADME profiles. As a result, 20 chemical compounds were selected for further biological evaluation, of which 13 were the Schiff bases of isoniazid. To diversify the set of selected compounds we applied substructure filtering and selected an additional 10 compounds, none of which were Schiff bases of isoniazid. Thirty compounds selected using virtual screening were biologically evaluated in a REMA assay against the M. tuberculosis strain H37Rv. Twelve compounds demonstrated MIC below 20 µM (ranging from 2.17 to 16.67 µM) and 18 compounds demonstrated substantially higher MIC values. The discovered antimycobacterial agents represent different chemical classes. [ABSTRACT FROM AUTHOR]

This study focuses on the synthesis of novel vinpocetine derivatives (2–25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as 1H NMR, 13C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC50 value of 3.53 ± 0.25 μM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC50 = 2.08 ± 0.16 μM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π–π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand–protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development. [ABSTRACT FROM AUTHOR]

Herein, we report the in vitro Acetylcholinesterase (AChE) inhibitory activities of imidazo[2,1-b]thiazole derivatives bearing thiosemicarbazide moiety. The compounds were characterized by diverse spectral methods and reported by our research team previously. As a novelty we conducted in vitro AChE inhibitory activities of the title compounds and performed in silico studies to provide insight related to activity mechanism of the compounds. Compound 4f displayed the best biological activity within our compounds with 69.92% enzyme inhibition value (at a final concentration of 0.08 mg/mL) and 0.0245 mg/mL IC50 value. [ABSTRACT FROM AUTHOR]

Virtual screening is emerging as a highly applied technique and gained prominence as widely used method for the search and identification of potential hits, significantly reducing the time needed to discover novel and effective compounds compared to high-throughput screening. Recently, the superiority of simulations with multiple programs compared to a single software docking has been discussed. The aim of this work was to apply consensus docking, molecular mechanics/generalized Born surface area (MM/GBSA) free binding energy recalculations, and in vitro evaluations on an in-house dataset of recently synthesized pyrrole-based hydrazide-hydrazones in the search for novel acetylcholinesterase (AChE) inhibitors. Two licensed softwares - GOLD 5.3 and Glide, were employed for the virtual screenings, and several chemotherapeutic potential hits were identified. Furthermore, MM/GBSA free binding energy recalculations were provided to enhance the robustness of the in silico results. The MM/GBSA scores of the top ten pyrrole-based hydrazide-hydrazones were ranging from -60.44 to -70.93 Kcal/mol. Subsequent, in vitro evaluations of the top ranked compounds revealed that 12d exhibited the highest AChE inhibitory activity, with a 55% inhibition rate at a concentration of 10 μM. Moreover, this prominent pyrrole-based AChE inhibitor formed stable complex with the active site of the enzyme. Interactions with the active amino residues Tyr72 and Tyr286 indicated that 12d was located near the peripheral anionic site of the enzyme. Additionally, in silico ADME investigations using QikProp demonstrated that 12d possesses optimal pharmacokinetic properties. In conclusion, this study identified a novel pyrrole-based AChE inhibitor 12d through a combination of computational and experimental findings. [ABSTRACT FROM AUTHOR]

Formaldehyde, sulfuric acid and salicylic acid were combined to create a 3,3′-methylenebis(2-hydroxybenzoic acid) (MHB) ligand, which was subsequently permitted to bind with zinc(II) ions. The ligand and its zinc(II) complex (Zn–MHB) have been described by a combination of elemental analyses, spectral analyses (UV–Vis, IR, MS and NMR), XRD, TEM, as well as TGA measurement. The ligand has been suggested to coordinate to the zinc center in a tetradentate manner forming the binuclear tetrahedral complex. An X-ray analysis indicated a considerable difference between MHB (crystalline) and Zn–MHB (amorphous). The UV–Vis spectra were used to determine the optical properties such as bandgap, refractive index, optical conductivity and penetration depth. The possibility of employing the samples for optoelectronic applications was indicated from the band gap values which underlie the range of semiconductors. TEM revealed the spherical shapes and mutation of ligand particles into the nano-scale by complexation. The antimicrobial potential of the MHB towards Gram-positive and Gram-negative bacterial growths has been investigated. The results suggested that it would be possible to employ MHB to prevent bacterial development, particularly that of salmonella typhimurium. The cytotoxicity of the MHB was assessed against two types of mammalian cells: VERO (the kidney of an African green monkey) and HFB4 (human skin melanocytes). Lower sensitivity was observed in VERO cells. [ABSTRACT FROM AUTHOR]

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As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure–activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1–4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC50 = 17.64 ± 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs. [ABSTRACT FROM AUTHOR]

The Dongyu River is a national site for monitoring the inflow of Nansi Lake, located in the southwest of Shandong Province, China. Water quality has a significant impact on the safety of the South-to-North Water Diversion Project. To investigate the water quality of Dongyu River and the estuary area of Nansi Lake, we collected water samples and surface sediments from Dongyu River and the estuary area in May 2019 and analysed the characteristics of the diatom communities and water quality. The results showed that 23026 diatom shells were identified at 15 sampling points in the study area, belonging to 161 species of 23 genera. The dominant diatom taxa were Cyclotella meneghiniana, Fragilaria fasciculata, Fragilaria ulna, Amphora libyca, and Cocconeis placentula. Redundancy analysis explained 43.2% of diatom change information. The Monte Carlo permutation test showed that NH4+-N and DO were significant environmental factors that affected diatom assembly, explaining 34.78% and 8.38% of the diatom variability, respectively. The results of the biological evaluation showed that the water quality of Dongyu River and the estuary area of Nansi Lake were in a light-medium pollution state. The RDA analysis of the diatom community and principal component analysis showed that the water quality of the middle and lower reaches of Dongyu River was poor. In general, the middle and lower reaches of Dongyu River are severely polluted by agricultural non-point sources and controlling the use of nitrogen and phosphorus fertilisers and the emission of nitrogen-containing organic matter can preserve the aquatic water quality of Dongyu River and the water safety of the East Route of the South-to-North Water Transfer Project. [ABSTRACT FROM AUTHOR]

This paper aimed to investigate the selected physicochemical and biological properties of titanium dioxide thin films deposited by atomic layer deposition on 316LVM stainless steel dedicated for cardiovascular implants. The main challenge in surface modification of these implants is the complexity of the processes taking place in the circulatory system. The atomic layer deposition was carried out for a number of cycles 500 and temperature 200 °C for 316LVM stainless steel substrate. The surface topography and surface microstructure were examined. Mouse fibroblasts L929 and Human Dermal Fibroblasts (NHDF-Ad) were used for cytotoxicity assays. The following biocompatibility aspects were investigated in vitro: direct cytotoxicity, hemolysis, platelet activation and aggregation, and pro-inflammatory cytokine levels. The titanium dioxide thin films inherited the substrate topography. The surface microstructure was amorphous with the typical layer by layer growth. The film improved the in vitro cell response in terms of cell viability. The cells were also able to proliferate and adhere; however, differences in the cell morphology and the distribution of cell nuclei were observed. The host cell damage was not noted in terms of lactate dehydrogenase levels. The proposed surface modification reduced the hemolysis index and did not significantly affect platelet activation and aggregation. Acute cytotoxicity of the thin films is not predicted basing on the in vitro pro-inflammatory cytokine assay. The results of the biological tests may be basis for further biological assessment proving the full biocompatibility of the proposed surface modification dedicated for specific cardiovascular implants. [ABSTRACT FROM AUTHOR]

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks.Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers.Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 μM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties.Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study’s mechanistic exploration, highlighting B7’s simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

A new Schiff base, 1-(E)-(4-((E) 4nitrobenzylidene) amino) phenyl)imino) methyl)naphthalen-2-ol (4NMN), was prepared from the reaction of p-phenylenediamine with 2-hydroxy-1-naphthaldehyde and 4-nitrobenzaldehyde and characterized with spectroscopic analysis. UV-VIS and NMR. Frontier molecular orbitals, molecular electrostatic potential, and chemical reactivity descriptors of the synthesized compound were studied using molecular modeling methods. The antibacterial and antifungal activities of the Schiff base were studied for its minimum inhibitory concentration. The compound showed a higher effect on yeast than against bacteria. Density functional theory (DFT) calculations were performed to study the mechanism of reaction for the synthesis of 4NMN, and the results were consistent with the experimental findings. 4NMN exhibited moderate antibacterial and antifungal activities and demonstrated higher inhibition potential against different resistant strains compared to the reference drug gentamycin. The absorption and fluorescence spectra of 4NMN were measured in different solvents, and the effect of relative polarity and acidity on the medium was observed. An inner filter effect was observed at high concentrations, and the compound showed considerable fluorescence enhancement with increasing medium viscosity and fluorescence quenching by the addition of traces of Cr1+ and Cu2+. Additionally, molecular docking studies were conducted to investigate the efficiency of antibacterial and antifungal targets.

In this study, choline chloride/urea was used as a green deep eutectic solvent in the three-component reaction of hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrazole derivatives, and in the four-component reaction of methyl/ethyl acetoacetate, hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrano[2,3-c]pyrazole derivatives. Elemental analysis, 1H, and 13C NMR spectroscopy were used to confirm the structure of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives. The antimicrobial effects of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives were investigated. In antimicrobial tests, instructions from clinical and laboratory standards institutes were used. Antimicrobial study was done on pathogenic gram-positive and gram-negative species, and specialized aquatic strains and fungal species. Using choline chloride/urea, novel pyrazole derivatives and pyrano[2,3-c]pyrazole derivatives were synthesized, and other derivatives were synthesized with higher efficiency in less time than some previously reported methods. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) obtained for derivatives were higher than some antibiotic drugs. Synthesis and reports of new derivatives of pyrazole and pyrano[2,3-c]pyrazole, and investigation and reports of their antimicrobial properties on gram-positive, gram-negative, and specialized aquatic and fungal species are among the novel and important findings of this study.

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure–activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1–4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC50 = 17.64 ± 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs.

Bromo, Nitro, Dichloro, Amino Substituted Carboxylate Derivatives of Thiophenes[a=2-bromo, b=4-nitro,d=2,4-dichloro, f=3-amino] have been synthesized by using Gewald reaction under mild reaction conditions. The obtained products were analyzed by IR, 1HNMR, 13C NMR, and Mass spectroscopy techniques. These compounds have explored binding affinity against GlcN-6-P synthesis. Taking into account factors such as docking energy, binding energy, inhibition constant and intermolecular energy, molecular docking determined the optimal potential conformations for the compounds obtained. Synthesized compounds NR3 and NR6 exhibited the lowest binding energy compared to the standard fluconazole. In vitro, biological studies such as antibacterial, antifungal, antidiabetic, and anti-inflammatory properties were investigated for the synthesized compounds NR3, NR4, NR6, and NR8. The compounds showed significant antibacterial, antifungal, antidiabetic, and anti-inflammatory activities. The results showed that almost all synthesized compounds were more potent against Bacillus cereus and Candida albicans than the standard drugs Ciprofloxacin and Itraconazole. [ABSTRACT FROM AUTHOR]

The 2-[2-(1-(4-chlorophenyl)ethylidene]hydrazineyl-1,3-thiazolidin-4-one (V) compound was synthesized via the condensation of thiosemicarbazone derivatives (III) with chloroacetyl chloride which gave a 1,3-disubstituted thiourea derivative (IV) as an intermediate compound, this was followed by cyclization of (IV) in situ boiling ethanol solvent in the presence of anhydrous potassium carbonate. The treatment of thiazole derivative (V) with 4-hydroxybenzaldehyde yielded the corresponding 2,5-disubstituted-1,3-thiazolidin-4-one (VI). Compound (VI) was reacted with 4-chlorophenacyl bromide that afforded 5-(4-hydroxybenzylidene)-2-(1,2-disubstituted) hydrazineyl-1,3-thiazolid-in-4-one (VIII). Acetylation of compounds (VI) and (VIII) with acetic anhydride formed acetyl derivatives (VII) and (IX). The structures of synthesized compounds were characterized and confirmed based on spectroscopic methods and microanalytical method (elemental analysis). It was found that most of the 1,3-thiazole derivatives (V–IX) showed enzyme activity, while compound (VIII) exhibited an excellent activity with IC50 value (4.22 μM) for α-amylase. Also, compound (VIII) gave a good inhibitory activity against free radical scavenging (DPPH), DPP-4, and human breast cancer (MCF-7). Based on the achieved results, it was suggested that compound (VIII) acts as a vital structure for the development of the most potent α-amylase inhibitors. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the chemical composition of the essential oils (EOs) from two Diplophyllum species and to evaluate their bioactivity potential [antimicrobial, antioxidant, anti-urease, anti-xanthine oxidase (XO)], and phenolic compounds. The analysis of Diplophyllum albicans and Diplophyllum taxifolium permitted the identification of 62 components, comprising ≥ 99.6% of the total EO composition. The major components found in these liverwort species were β-patchoulene, β-santalene, β-himachalene, and cubebol. The antimicrobial assays showed that the solvent extracts (n-hexane and methanol) from these liverwort species exhibited weak to moderate antimicrobial activity. In addition, the methanol extracts of these liverwort species also exhibited moderate to high antioxidant potential. The enzyme inhibitory effects of the species were determined using urease and XO for the methanol extracts. Generally, the methanol extracts of D. albicans and D. taxifolium exhibited powerful urease inhibition with IC50 values of 9.711 ± 0.058 and 6.304 ± 0.099 µg/mL, respectively, compared to the IC50 value of 26.124 ± 0.077 µg/mL for the standard (acetohydroxamic acid). Moreover, the HPLC-UV detection method showed that the analysed methanol extracts of these liverwort species contained only catechin and benzoic acid. These findings suggest that the analysed liverwort species possess antioxidant and urease inhibition, thus indicating the potential to explore new bioactive molecules.

Human activities are the main cause of river pollution that continuously affect the water quality of the rivers. In this study, the population structure of macroinvertebrates was investigated as a biological indicator for water quality in the Khorram-rud River. For this purpose, a number of 4 stations were selected and some physicochemical parameters along with macroinvertebrates sampling were done monthly for 12 months (December 2018- November 2019) in each station. Totally 26 families in 14 orders of macroinvertebrates with the domination of families Chironomidae, Baetidae, and Tricorythidae, respectively were found. The results of physicochemical factors showed that the lowest and highest water temperatures recorded were 8.66 ± 0.57 in December and 23.66 ± 0.57 in July, respectively, the maximum average dissolved oxygen in March 5.83 ± 0.28 mg/l in the station (1), and the minimum was 0/00 mg/l in a station(4). pH value recorded with a minimum of 6 ± 0.86 in January and a maximum of 8 ± 0/00 in June. The average change of nitrite in different stations showed a slight fluctuation but was higher than the allowable limit in all stations. The highest amount of nitrate in a station (3) in June was 36.66 ± 5.77 and the lowest in a station (1) in December recorded as 2 ± 0/00 mg/l. The seasonal variations in density of macroinvertebrates indicate the maximum density in autumn and the minimum density in winter. The results based on (BMWP, ASPT) and richness and diversity indices (Shannon-Weiner, Margalef) indicated that the Khorram-rud river water is in the contaminated water class.

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.

The objective of this study is to design and synthesize substituted η6-chromium(0) tricarbonyl metal complexes carrying o-carborane units as potential boron neutron capture therapy (BNCT) agents. In this study, 1,2-diphenyl-o-carborane (1) units were used as starting materials to generate biologically active species. We investigated how the structural changes of 1 substituted with chromium(0) tricarbonyl affect the biological properties, and 1-(Phenyl-η6-chromium(0) tricarbonyl)-2-phenyl-o-carborane (2) and 1,2-bis(phenyl-η6-chromium(0) tricarbonyl)-o-carborane (3) species were produced in moderate yields. The molecular structures of compounds 1–3 were identified and established by infrared (IR); 1H, 11B, and 13C nuclear magnetic resonance (NMR) and X-ray crystallography analyses. Crystal structures of 1,2-diphenyl-o-carborane and the corresponding chromium complexes 1, 2, and 3 were obtained. In an in vitro study using B16 and CT26 cancer cells containing the triphenyl-o-carboranyl chromium(0) complexes Ph3C2BCr2 and Ph3C2BCr3, which we reported previously, compounds 2 and 3 accumulated at higher levels than compounds Ph3C2BCr2 and Ph3C2BCr3. However, the phenylated o-carboranyl chromium complexes have been found to be more cytotoxic than p-boronophenylalanine (BPA). [ABSTRACT FROM AUTHOR]

Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment. [ABSTRACT FROM AUTHOR]

Methylated gallic acid (MGA) is a potent anticancer biomolecular entity (BME). Loading MGA into a nano-vesicular (NV) drug delivery system using nanotechnology approaches can increase the efficiency of the drug and its release characteristics. This study aimed to develop an ethosomal nano-vesicular (ENV) system loaded with MGA that shows augmented entrapment efficiency, release rate, and cytotoxic potential against oral cancer. The ENV system was synthesized using Soy lecithin, ethanol, and propylene glycol. The ENV system's characterization (DLS, Zeta potential, TEM, FT-IR) with and without MGA was performed. The cytotoxicity evaluation of MGA alone compared to the MGA-loaded ENV system was performed against the squamous cell carcinoma—9 (SCC-9) cell line. The DLS and zeta potential analysis revealed the size of the ENV system as 58.2 nm and—43.5 mV charge, respectively. MGA loading to ENV system increased size to 63 nm and decreased charge to −2.8 mV. Peaks of FTIR analysis confirmed the encapsulation of MGA in the ENV system. TEM studies revealed the spherical surface morphology of the MGA-loaded ENV system. Compared with conventional MGA alone administration, ENV loaded with MGA showed better drug absorption and bioavailability in vitro. Furthermore, the entrapment efficiency, in vitro drug release, and cytotoxicity results firmly establish the improved therapeutic potential of ENV loaded with MGA against oral cancer cells than MGA alone. [ABSTRACT FROM AUTHOR]

Introduction: Schizophrenia is a serious mental illness that requires effective treatment with minimal adverse effects. As preclinical and clinical research progresses, trace amine-associated receptor 1 (TAAR1) is becoming a potential new target for the treatment of schizophrenia. Methods: We used molecular docking and molecular dynamics (MD) simulations to discover TAAR1 agonists. The agonistic or inhibitory effects of compounds on TAAR1, 5-HT1A, 5-HT2A, and dopamine D2-like receptors were determined. We used an MK801-induced schizophrenia-like behavior model to assess the potential antipsychotic effects of compounds. We also performed a catalepsy assay to detect the adverse effects. To evaluate the druggability of the compounds, we conducted evaluations of permeability and transporter substrates, liver microsomal stability in vitro, human ether-à-go-go-related gene (hERG), pharmacokinetics, and tissue distribution. Results: We discovered two TAAR1 agonists: compounds 50A and 50B. The latter had high TAAR1 agonistic activity but no agonistic effect on dopamine D2-like receptors and demonstrated superior inhibition of MK801-induced schizophrenia-like behavior in mice. Interestingly, 50B had favorable druggability and the ability to penetrate the blood-brain barrier (BBB) without causing extrapyramidal symptoms (EPS), such as catalepsy in mice. Conclusion: These results demonstrate the potential beneficial role of TAAR1 agonists in the treatment of schizophrenia. The discovery of a structurally novel TAAR1 agonist (50B) may provide valuable assistance in the development of new treatments for schizophrenia. [ABSTRACT FROM AUTHOR]

Methods of the synthesis and the investigation of the properties of unnatural seven-memebered cyclic sugars and nucleosides, are of high interest. Septanoses provide conformationally more flexible sugars and due to their similarity to natural carbohydrates they have interesting and potentially useful physical, chemical, and biological properties. Additionally, nucleosides with seven-membered sugar moiety are commonly found in natural products and biologically active molecules. Modification of such nucleosides hold great promise as therapeutic agents. The present review describes the chemical synthesis and biological properties of septanoses as well as nucleosides containing septanosyl moieties. [ABSTRACT FROM AUTHOR]

This work describes the synthesis of a novel multiple dentation azo‐Schiff base dye 2‐((3‐((5‐chlorobenzo[d]oxazol‐2‐yl)diazenyl)‐4‐hydroxybenzylidene)amino)pyridin‐3‐ol (H2L) based mixed heterocyclic bnzoxazole and pyridine moieties in facile two successive steps approach. Firstly is the synthesis of start azo dye 3‐((5‐chlorobenzo[d]oxazol‐2‐yl)diazenyl)‐4‐hydroxybenzaldehyde (CBOAHB) followed by condensation with 3‐hydroxy 2‐amino pyridine. It's novel binuclear Ni (II), Cu (II), Ru (III), and Zr (IV) 2:1 metal‐to‐ligand stoichiometric complexes were synthesized and characterized via various spectroscopic and analytical techniques. The data showed the paramagnetic Ni2+ complex has tetrahedral geometry, while the Cu2+, Ru3+, and diamagnetic Zr4+ complexes have octahedral geometrical structures. Data of the crystallinity, morphology, and average particle size showed that Cu2+ and Ru3+ complexes were formed at the nanoscale. The geometrical structures according to 3D molecular modeling are in good agreement with those proposed by the experiments. The azo start CBOAHB, H2L, and its metal complexes have been examined for their biological and catalytic features. The Zr4+ complex manifested higher antibacterial activity against Staphylococcus aureus(S. aureus), the ligand H2L exhibited higher antibacterial activity against Escherichia coli (E. coli), and the Ni2+ complex showed higher antifungal activity against Candida albicans (C. Albicans). The anticancer activity was evaluated against human hepatocellular carcinoma (HepG‐2), colorectal carcinoma (HCT‐116), and human breast carcinoma (MCF‐7). The ligand H2L has very strong cytotoxicity toward HepG‐2 cells, Ni (II) complex has the strongest cytotoxicity against HCT‐116 cells and Zr (VI) has the strongest cytotoxicity against MCF‐7 cells. The findings of antioxidant activity are in perfect accord with those obtained from anticancer. The heterogeneous catalytic activity was examined for the reduction of Direct Blue 14 dye. Ru (III) complex and Cu (II) complex achieved the highest catalytic activity with the highest degradation % and within a very short time did not exceed 3 min. [ABSTRACT FROM AUTHOR]

Simple Summary: Sophoridine, a natural quinolizidine alkaloid with biological activities, was isolated and identified from traditional medicinal herbs. Although mosquitoes can be effectively controlled by chemical insecticides, their intense use has significantly increased the development and spread of resistant mosquitoes. Chemical insecticides have negative effects, such as potential health risks, water contamination, environmental pollution, and toxicity to nontarget organisms, including people. In this study, two series of sophoridine derivatives were generated using sophoridine as the lead compound. All derivatives were characterized and screened for their insecticidal activity against larva and adult mosquitoes. Their effects on the growth cycle of larva and their action on AChE from Aedes albopictus were also explored. Finally, morphological studies of the derivative-treated dead larvae were conducted. Two series of novel sophoridine derivatives were designed, synthesized, and evaluated for their anti-mosquito activity. SOP-2g, SOP-2q, and SOP-2r exhibited potential larvicidal activity against Aedes albopictus larva with LC50 values of 330.98, 430.53, and 411.09 ppm, respectively. Analysis of structure–activity relationships indicated that the oxime ester group was beneficial for improving the larvicidal biological activity, whereas the long-chain aliphatic group and fused-ring group were introduced. Furthermore, the larvicidal mechanism was also investigated based on the inhibition assay of acetylcholinesterase (AChE) and the morphological observation of dead larva treated with derivatives. Results indicated that the AChE inhibitory activity of the preferred three derivatives were 63.16%, 46.67%, and 35.11%, respectively, at 250 ppm concentration. Additionally, morphological evidence demonstrated that SOP-2q and SOP-2r induced changes in the larva's intestinal cavity, caudal gill, and tail, thereby displaying larvicidal action against Ae. albopictus together with AChE inhibition. Therefore, this study implied that sophoridine and its novel derivatives could be used to control the population of mosquito larva, which may also be effective alkaloids to reduce the mosquito population density. [ABSTRACT FROM AUTHOR]

The discovery and development of new drugs are extremely long and costly processes. Recent progress in artificial intelligence has made a positive impact on the drug development pipeline. Numerous challenges have been addressed with the growing exploitation of drug-related data and the advancement of deep learning technology. Several model frameworks have been proposed to enhance the performance of deep learning algorithms in molecular design. However, only a few have had an immediate impact on drug development since computational results may not be confirmed experimentally. This systematic review aims to summarize the different deep learning architectures used in the drug discovery process and are validated with further in vivo experiments. For each presented study, the proposed molecule or peptide that has been generated or identified by the deep learning model has been biologically evaluated in animal models. These state-of-the-art studies highlight that even if artificial intelligence in drug discovery is still in its infancy, it has great potential to accelerate the drug discovery cycle, reduce the required costs, and contribute to the integration of the 3R (Replacement, Reduction, Refinement) principles. Out of all the reviewed scientific articles, seven algorithms were identified: recurrent neural networks, specifically, long short-term memory (LSTM-RNNs), Autoencoders (AEs) and their Wasserstein Autoencoders (WAEs) and Variational Autoencoders (VAEs) variants; Convolutional Neural Networks (CNNs); Direct Message Passing Neural Networks (D-MPNNs); and Multitask Deep Neural Networks (MTDNNs). LSTM-RNNs were the most used architectures with molecules or peptide sequences as inputs. [ABSTRACT FROM AUTHOR]

PLK-1 (Polo-like kinase-1) plays an essential role in cytokinesis, and its aberrant expression is considered to be keenly associated with a wide range of cancers. It has been selected as an appealing target and small-molecule inhibitors have been developed and studied in clinical trials. Unfortunately, most have been declared as failures due to the poor therapeutic response and off-target toxicity. In the present study, a novel potent PLK-1 inhibitor, compound 7a, was designed and synthetized. 1H NMR, 13C NMR, 19F NMR and mass spectrum were comprehensively used for the compound characterization. The compound exhibited higher potency against PLK-1 kinase, HCT-116 and NCI-H2030 cell lines than the positive control. Molecular docking indicated that the binding mode that the ATP binding site of PLK-1 was occupied by the compound. Then, a UHPLC-MS/MS method was established and validated to explore the pharmacokinetic behavior of the drug candidate. The method had good selectivity, high sensitivity and wide linearity. The exposure increased linearly with the dose, but the oral bioavailability was not satisfactory enough. Then, the metabolism was studied using liver microsomes by UHPLC-Q-Orbitrap/HRMS. Our research first studied the pharmacokinetic metabolic characteristics of 7a and may serve as a novel lead compound for the development of PLK-1 inhibitors. [ABSTRACT FROM AUTHOR]

Natural extracts have been and continue to be used to treat a wide range of medical conditions, from infectious diseases to cancer, based on their convenience and therapeutic potential. Natural products derived from microbes, plants, and animals offer a broad variety of molecules and chemical compounds. Natural products are not only one of the most important sources for innovative drug development for animal and human health, but they are also an inspiration for synthetic biology and chemistry scientists towards the discovery of new bioactive compounds and pharmaceuticals. This is particularly relevant in the current context, where antimicrobial resistance has risen as a global health problem. Thus, efforts are being directed toward studying natural compounds' chemical composition and bioactive potential to generate drugs with better efficacy and lower toxicity than existing molecules. Currently, a wide range of methodologies are used to analyze the in vitro activity of natural extracts to determine their suitability as antimicrobial agents. Despite traditional technologies being the most employed, technological advances have contributed to the implementation of methods able to circumvent issues related to analysis capacity, time, sensitivity, and reproducibility. This review produces an updated analysis of the conventional and current methods to evaluate the antimicrobial activity of natural compounds. [ABSTRACT FROM AUTHOR]

Numerous food organizations have identified excessive calorie consumption and accompanying ailments as significant health risks associated with high sugar consumption. Administering stevioside (ST), sucralose (SU), and the two synergically (SU+ST) affected normal rats' weight gain. In the current study, SU showed the highest undesired effect. Indeed, administering the three treatments to diabetic rats (DR) did not improve the rats' weight gain. Although, insulin injection synergically with the treatments improved the weight gain, as recorded after three weeks. The best-improving rate was observed in the ST group. After the administration of ST and ST+SU to the DR, the blood glucose level (GL) was positively affected, with SU having no effects on reducing the GL. A considerable reduction in serum insulin (SIL) was noted in the DR+SU group. On the contrary, ST did not negatively affect the SIL, rather an improvement was recorded. In addition, giving SU did not significantly affect the ALT level in the DR or normal rats (NR). A significant improvement in total bilirubin (TBILI) was observed when insulin was injected with ST or SU in DR groups. Further, triglycerides (TG) after administering ST, SU, or ST+SU to NR had no significant difference compared to the control group (NR). Although, the three treatments markedly but not significantly lowered TG in the DR. For total cholesterol (CHO), both DR and NR had no significant effect after the three treatments. No histopathological alterations were recorded in the NR group. Diffuse and severe atrophy of the islands of Langerhans due to depletion of their cells and mild papillary hyperplasia of the pancreatic ducts were represented by a slightly folded ductal basement membrane and newly formed ductules in STZ-DR. Simultaneous atrophy and absence of the cells of islands of Langerhans besides ductal hyperplasia were evident in DR+SU. Hyperplastic ductal epithelium and atrophic Langerhans cells were seen in DR+SU+In. Degeneration and mild atrophy were observed in the islands of Langerhans structures. There was essentially no noticeable change after utilizing ST. A slight shrinkage of the Langerhans' islets was detected in DR+ST. In DR+ST+In, no histopathological alterations in the islands of Langerhans were recorded. Congestion in the stromal blood vessels associated with degenerative and necrotic changes in the cells of the islands of Langerhans in DR+SU+ST was observed. In NR+SU, congestion of the blood vessels associated with mild atrophy in the islands of Langerhans and dilatation in stromal blood vessels was noticed. In conclusion, ST is safe, and SU should be taken cautiously, such as mixing with ST and/or taken at a very low concentration to avoid its drastic effect on the human body. [ABSTRACT FROM AUTHOR]

In order to achieve smart biomedical micro/nanomaterials, promote interaction with biomolecules, improve osteogenic/chondrogenic differentiation, exhibit better dispersion in bone implants and ultimately maximize functionality, we innovatively and successfully designed and synthesized polymer PBLG-modified GdPO4·H2O nanobunches by hydroxylation, silylation and glutamylation processes. The effects of different feeding ratios on the surface coating of GdPO4·H2O with Si-OH, the grafting γ-aminopropyltriethoxysilane (APS) and the in situ ring-opening polymerization reaction of poly(g-benzyl-L-glutamate) (PBLG) were investigated, and the physical and chemical properties were characterized in detail. When GdPO4·H2O@SiO2–APS:NCA = 4:1, the PBLG-g-GdPO4·H2O grafting rate was 5.93%, with good stability and dispersion in degradable polymeric materials. However, the MRI imaging signal was sequentially weakened as the modification process proceeded. Despite this, the biological effects had surprising findings. All the modifiers at appropriate concentrations were biocompatible and biologically active and the biomacromolecules of COL I and COL II in particular were expressed at least 3 times higher in GdPO4·H2O@SiO2 compared to the PLGA. This indicates that the appropriate surface modification and functionalization of gadolinium-containing micro/nanomaterials can promote interaction with cells and encourage bone regeneration by regulating biomacromolecules and can be used in the field of biomedical materials. [ABSTRACT FROM AUTHOR]

AbstractThe Dongyu River is a national site for monitoring the inflow of Nansi Lake, located in the southwest of Shandong Province, China. Water quality has a significant impact on the safety of the South-to-North Water Diversion Project. To investigate the water quality of Dongyu River and the estuary area of Nansi Lake, we collected water samples and surface sediments from Dongyu River and the estuary area in May 2019 and analysed the characteristics of the diatom communities and water quality. The results showed that 23026 diatom shells were identified at 15 sampling points in the study area, belonging to 161 species of 23 genera. The dominant diatom taxa were Cyclotella meneghiniana, Fragilaria fasciculata, Fragilaria ulna, Amphora libyca, and Cocconeis placentula. Redundancy analysis explained 43.2% of diatom change information. The Monte Carlo permutation test showed that NH4+-N and DO were significant environmental factors that affected diatom assembly, explaining 34.78% and 8.38% of the diatom variability, respectively. The results of the biological evaluation showed that the water quality of Dongyu River and the estuary area of Nansi Lake were in a light-medium pollution state. The RDA analysis of the diatom community and principal component analysis showed that the water quality of the middle and lower reaches of Dongyu River was poor. In general, the middle and lower reaches of Dongyu River are severely polluted by agricultural non-point sources and controlling the use of nitrogen and phosphorus fertilisers and the emission of nitrogen-containing organic matter can preserve the aquatic water quality of Dongyu River and the water safety of the East Route of the South-to-North Water Transfer Project.