Compound 5a Research Articles

Crystal structures of ten phosphane chalcogenide complexes of gold(III) chloride and bromide.

The structures of ten phosphane chalcogenide complexes of gold(III) halides, with general formula R 1 3-n R 2 nPEAuX 3 (R 1 = t-butyl; R 2 = i-propyl; n = 0 to 3; E = S or Se; X = Cl or Br) are presented. The eight possible chlorido derivatives are: 9a, n = 3, E = S; 10a, n = 2, E = S; 11a, n = 1, E = S; 12a, n = 0, E = S; 13a, n = 3, E = Se; 14a, n = 2, E = Se; 15a, n = 1, E = Se; and 16a, n = 0, E = Se, and the corresponding bromido derivatives are 9b-16b in the same order. Structures were obtained for 9a, 10a (and a second polymorph 10aa), 11a (and its deutero-chloro-form monosolvate 11aa), 12a (as its di-chloro-methane monosolvate), 14a, 15a (as its deutero-chloro-form monosolvate 15aa, in which the solvent mol-ecule is disordered over two positions), 9b, 11b, 13b and 15b. The structures of 11a, 15a, 11b and 15b form an isotypic set, and those of compounds 10aa and 14a form an isotypic pair. All structures have Z' = 1. The gold(III) centres show square-planar coordination geometry and the chalcogenide atoms show approximately tetra-hedral angles (except for the very wide angle in 12a, probably associated with the bulky t-butyl groups). The bond lengths at the gold atoms are lengthened with respect to the known gold(I) derivatives, and demonstrate a considerable trans influence of S and Se donor atoms on a trans Au-Cl bond. Each compound with an isopropyl group shows a short intra-molecular contact of the type C-Hmethine⋯Xcis; these may be regarded as intra-molecular 'weak' hydrogen bonds, and they determine the orientation of the AuX 3 groups. The mol-ecular packing is analysed in terms of various short contacts such as weak hydrogen bonds C-H⋯X and contacts between the heavier atoms, such as X⋯X (9a, 10aa, 11aa, 15aa and 9b), S⋯S (10aa, 11a and 12a) and S⋯Cl (10a). The packing of the polymorphs 10a and 10aa is thus quite different. The solvent mol-ecules take part in C-H⋯Cl hydrogen bonds; for 15aa, a disordered solvent region at z ≃ 0 is observed. Structure 13b involves unusual inversion-symmetric dimers with Se⋯Au and Se⋯Br contacts, further connected by Br⋯Br contacts.

Synthesis, Solvatochromic Studies, DFT Calculations, Characterization, and In Silico Molecular Docking Studies of Azo Dyes of 3‐Methyl‐1‐phenyl‐1H‐pyrazol‐5‐amine

AbstractIn this work, the four azo dyes (A1–A4) were synthesized using 5‐amino‐3‐methyl‐1‐phenyl pyrazole with four different coupling components by the conventional, simple diazo‐coupling method. These synthesized azo molecules were confirmed by various spectroscopic methods viz, FT‐IR spectra, HR‐MS spectra, 1H NMR spectra, and 13C NMR spectra. The electronic absorption and fluorescence spectra of synthesized azo compounds were recorded at room temperature, with different solvents. The DFT calculations were performed using 6‐311++G (d, p) basis set to evaluate the global reactive parameters of the synthesized azo dyes. The anti‐microbial activities were studied; the compound A1 exhibited a good antibacterial and anti‐fungal activities. The study of in silico molecular docking of the azo compounds revealed that all the compounds found to possess were extraordinary binding affinity as compared to the standards. The anti‐tuberculosis study was carried against mycobacterium tuberculosis and the results have shown that, the compound A2 showed good sensitivity to the studied azo compounds.

Pyrrole‐Thiazolidin‐4‐one Analogues Exhibit Promising Anti‐Tuberculosis Activity

AbstractA series of pyrrole‐thiazolidin‐4‐one conjugates were synthesized and evaluated for their anti‐mycobacterial and anti‐bacterial activities. Two compounds, 10 a and 10 k, were the most effective conjugates and produced identical MICs (0.5 μg/mL) against M. tuberculosis H37Rv with a high selectivity index. Upon evaluation against the ESKAP bacteria panel, compound 10 g emerged most effective against S. aureus (MIC=8.0 μg/mL) while compound 10 o produced activity against A. baumannii (MIC=4.0 μg/mL). A molecular docking study revealed that the most active compound 10 a has similar binding interactions as those of BM212 and rimonabant, with a comparable docking score against M. tuberculosis mycolic acid transporter MmpL3.

Structure-based approaches for the design of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazoles as tubulin polymerization inhibitors

The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound 4, which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound 4, a series of novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazole derivatives (9a–9x) were developed by replacing a CH group in the 1H-benzo[d]imidazole skeleton of compound 4 with a nitrogen atom as a hydrogen bond acceptor. Among them, compound 9a showed the strongest antiproliferative activity with IC50 values ranging from 14 to 45 nM against three human cancer cell lines (MCF-7, SGC-7901 and A549), lower than that of compound 4. Mechanistic studies indicated that compound 9a could inhibit tubulin polymerization, destroy the microtubule skeleton, block the cell cycle in G2/M phase, induce cancer cell apoptosis, prevent cancer cell migration and colony formation. Moreover, compound 9a significantly inhibited tumor growth in vivo without observable toxicity in the mice 4T1 xenograft tumor model. In conclusion, this report shows a successful case of the structure-based design approach of a potent tubulin polymerization inhibitor for cancer treatment.

Synthesis and antibacterial activities of novel hybrid molecules based on benzothiazole, benzimidazole, benzoxazole, and pyrimidine derivatives, each connected to N-arylacetamide and benzoate groups

Novel benzimidazoles, benzothiazoles, and benzoxazoles linked to N-arylacetamide were synthesized in good yields by reacting a series of 2-oxo-2-(arylamino)ethyl 4-formylbenzoates with o-phenylenediamine, 2-aminothiophenol, or 2-aminophenol in ethanol at reflux in the presence of NaHSO3. Attempts to use the new aldehydes as adaptable precursors for the synthesis of fused dihydropyran or fused dihydropyridine via Michael or Hantzsch's reactions were unsuccessful; instead, the processes produced the corresponding arylidene derivatives. The structures of the novel compounds were verified with a variety of spectra. All synthesized compounds were evaluated for antibacterial activity against four different bacterial strains. Compound 6a had good activity against Escherichia coli in an agar diffusion assay, with an inhibitory zone width of 30 mm compared to ofloxacin (20 mm). Compounds 18a and 18b were most effective against Bacillus subtilis, with MICs of 156.3 and 312.5 µg/mL, respectively. Molecular docking investigations demonstrated that compounds 6a, 18a, and 18b had high binding affinities for bacterial tyrosyl-tRNA synthetase and DNA gyrase.

Synthesis and anticancer evaluation of new disulfides incorporating naphthalimide moiety

A series of new disulfides incorporating naphthalimide moiety were designed, synthesized and biologically evaluated against three human cancer cell lines (MCF-7, SMMC-7721 and Hela). Most of target compounds exhibited some degrees of anticancer activities, and some compounds displayed better effects than reference drugs PX-12 and 5-FU against the tested three cancer cells. Especially, compound 7d showed the most potent antiproliferative activity against MCF-7 cell lines with IC50 value of 3.19 μM. Compound 8a displayed prominent anticancer property against SMMC-7721 cell lines with IC50 value of 1.84 μM. Compound 6c possessed the most effective proliferation inhibitory activity against Hela cell lines with IC50 value of 2.14 μM. In addition, cytotoxicity evaluation indicated that most of the compounds had weak cytotoxicity to L929 cell lines.

Design, synthesis and bioactivity of a new class of antifungal amino acid-directed phthalide compounds.

Peanut southern blight disease, caused by Sclerotium rolfsii, is a destructive soil-borne fungal disease. The current control measures, which mainly employ succinate dehydrogenase inhibitors, are prone to resistance and toxicity to non-target organisms. As a result, it is necessary to explore the potential of eco-friendly fungicides for this disease. Fourteen novel phthalide compounds incorporating amino acid moieties were designed and synthesized. The in vitro activity of analog A1 [half maximal effective concentration (EC50) = 332.21 mg L-1] was slightly lower than that of polyoxin (EC50 = 284.32 mg L-1). It was observed that on the seventh day, the curative activity of A1 at a concentration of 600.00 mg L-1 was 57.75%, while the curative activity of polyoxin at a concentration of 300.00 mg L-1 was 42.55%. These results suggested that our compound exhibited in vivo activity. Peanut plants treated with A1 showed significant agronomic improvements compared to the untreated control. Several compounds in this series exhibited superior root absorption and conduction in comparison to the endothermic fungicide thifluzamide. The growth promotion and absorption-conduction experiments demonstrated the reason for the superior in vivo activity of the target compound. Cytotoxic assays have demonstrated that this series of targeted compounds exhibit low toxicity levels toward human lo2 liver cells. Our results provide a new strategy for the design and synthesis of novel green compounds. Furthermore, the target compound A1 can serve as a lead for further development of green fungicides. © 2024 Society of Chemical Industry.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 μM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Novel biologically active pyridine derivatives: Synthesis, structure characterization, in vitro antimicrobial evaluation and structure-activity relationship

The rate of microbial resistance has continued to rise significantly as the availability of new antibiotics has declined. A new series of pyridine and thienopyridine derivatives were designed, synthesized and tested as antimicrobial agents. The reaction of 4-bromo acetophenone and vetraldehyde (3,4-dimethoxy benzaldehyde) in ethanol and sodium hydroxide solution afforded the corresponding chalcone which was used as a suitable precursor to prepare a new series of pyridine derivatives. The treatment of the latter chalcone with 2-cyanothioacetamide afforded the corresponding pyridinethione which was used as a precursor to synthesize the targeted thienopyridine derivatives in good to excellent yield by the reaction with 2-chloro-N-arylacetamide derivatives, α-haloketones, methyl iodide or chloroacetonitrile in one or two steps. The structure of the synthesized compounds was confirmed chemically by their preparations with other pathways and their spectral data. The newly synthesized pyridine and thienopyridine derivatives exhibited good to strong antimicrobial activity against microbial strains E. coli, B. mycoides and C. albicans. With maximal antimicrobial activity against B. mycoides (33 mm) and C. albicans (29 mm), respectively, compounds 12a and 15 demonstrated the highest inhibition zone. Compound 12a prevented the growth of E. coli, at MIC level of 0.0195 mg/mL, and B. mycoides and C. albicans at MIC level below than 0.0048 mg/mL, respectively. Additionally, compound 15 prevented the visible growth of E. coli, B. mycoides, and C. albicans at MIC values of >0.0048, 0.0098, and 0.039 mg/mL, respectively. The relation between the chemical structure of the synthesized pyridine and thienopyridine compounds and their antimicrobial properties was discussed in the SAR study.

Novel tubulin polymerization inhibitors based on the hybridization of coumarin and indole ring: Design, synthesis and bioactivities evaluation

In order to find the potent tubulin polymerization inhibitors as anticancer drugs, a series of novel coumarin-indole derivatives were synthesized, and the bioactivity of these synthetic compounds was performed to elucidate the mechanism of anticancer activity. In vitro cell experiments indicated that among these compounds, 7a exhibited excellent inhibitory activities on MCF-7, A549 and HepG2 cells, having IC50 values ranging from 1.79 to 40.55 nanomolar, which was better than the positives cisplatin and colchicine. Tubulin polymerization inhibition assay found 7a could inhibit the polymerization of tubulin. Meanwhile, immunofluorescence staining of A549 cells showed that 7a targeted the tubulin to exert its anticancer activity. Additionally, compound 7a displayed significant inhibition of the wound-healing activity of A549 cells. The outcomes of flow cytometry demonstrated 7a could significantly halt the progression of the cell cycle during the G2/M phase and induce the apoptosis of A549 cells by reducing the mitochondrial membrane potential and increasing the level of ROS. Finally, molecular docking further demonstrated 7a could interact with tubulin.Collectively, the promising biological activity of 7a makes it valuable as further development of antitumor drugs.

Identification of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffolds as potent Lck inhibitors as anti-cancer agents

Lymphocyte-specific protein tyrosine kinase (Lck) plays vital roles in the T-cell receptor- mediated development, function, and differentiation of T-cells. Given its substantial involvement in T cell signaling, irregularities in the expression and functionality of Lck may lead to various diseases, including cancer. In this study, we found that compound 12a exerted significant inhibitory potency against Lck with an IC50 value of 10.6 nM. In addition, 12a demonstrated high efficacy in various colon cancer cell lines as indicated by GI50 values ranging from 0.24 to 1.26 μM. Notably, 12a inhibited the phosphorylation of Lck in Colo201 cells. Overall, the anti-proliferative effects of 12a on diverse cancer cell lines highlights its potential application for the treatment of various cancer types.

Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents. Communicated by Ramaswamy H. Sarma

Multistage in silico approach to identify novel quinoline derivatives as potential c-kit kinase inhibitors

The type II-C-KIT signaling network has been extensively studied for its potential as a target for cancer treatment, leading to the investigation of quinoline derivatives as compounds with inhibitory effects on c-Kit kinase. In this study, a multistage approach was employed, including the creation of pharmacophore models, 3D QSAR analysis, virtual screening, docking investigations, and molecular dynamics stimulation. The pharmacophore evaluation included a data set of 29 ligands, which resulted in the generation of the ADDHR_1pharmacophore model as the most promising, with a survival score of 5.6812. The main objective was to utilize the atom-based 3D-QSAR approach for generating robust 3D-QSAR models aimed at identifying new TypeII-C-kit kinase inhibitors. The evaluations of these models have convincingly demonstrated their high predictive power (Q2 = 0.6547, R2 = 0.9947). Using atom-based 3D-QSAR data, a total of 7564 novel compounds were generated from R-group enumeration. Molecular docking and MM-GBSA study revealed that compound A1 exhibited the highest binding score of −9.30 kcal/mol and a Δ GBind value of −90.56 kcal/mol. The ZINC compounds were then screened using the pharmacophore model, followed by virtual screening, which identified ZINC65798256, ZINC09317958, ZINC73187176, and ZINC76176670 as potential candidates with promising docking scores. Among these, ZINC65798256 demonstrated the best binding interactions with amino acid residues, ASP810, LYS623, CYS673, and THR670 (PDB ID: 1T46). To further analyze the structural features and molecular interactions, molecular dynamics simulation was conducted for a time scale of 100 ns. Communicated by Ramaswamy H. Sarma

Synthesis, characterization, anti-lung cancer activity, and in-silico studies of some novel triazole-based analogues as Pellizzari products

In the present research work, a series of novel (Z)-5-(cyclohexylidenehydrazono)-2-aryl-3H,5H-thiazolo[3,4-b][1,2,4]triazole derivatives were synthesized by Pellizzari reaction of (Z)-3-amino-2-(cyclo hexylidenehydrazono)thiazolidin-4-one with different aromatic amides. All the synthesized products were obtained in a good to excellent yields, and their structures were established based on UV-Vis, FT-IR, 1H NMR, 13C NMR, and HRMS analysis. To validate the experimental findings, in-silico studies of one synthesized compound (11a) were done with the help of density functional theory (DFT) at B3LYP/6-311++G(d,p) level. Frontier molecular orbitals, molecular electrostatic potential, and Reduced density gradient analysis were performed to better understand the electronic properties, and reactivity. Results of NLO, ELF, LOL, DOS, AIM, and vector analysis were reported. All the newly synthesized benzimidazole compounds had a cytotoxic impact, in some cases much more potent than the reference medication. The cytotoxicity of all the synthesized compounds were assessed against A549 cell lines using the MTT assay. Among them, compounds 11d and 11e showed more potent cytotoxicity having the IC50 value ∼90 and ∼80 µM, respectively. The molecular docking studies revealed an excellent affinity for the active sites of the matching gene regulation-inhibitor complex (BDR4) protein. Additionally, the evaluation of ADMET parameters indicated good pharmacokinetic properties of all the investigated compounds.

Synthesis of DOPO Derivatives for the Fabrication of Flame Retardant Epoxy Composites

Four flame retardant DOPO derivatives were succesfully synthesized by Pudovik reaction, including 6,6'-(([1,1'-biphenyl]-4,4'-diylbis(azanediyl))bis (thiophen-2-ylmethylene))bis(dibenzo[c,e][1,2]oxaphosphinine 6-oxide) 5a, 6,6'-(((sulfonylbis(4,1-phenylene))bis(azanediyl)) bis(thiophen-2-ylmethylene))bis(dibenzo[c,e][1,2]oxaphosphinine 6-oxide) 5b, 6,6'-((1,4-phenylenebis(azanediyl))bis(furan-2ylmethylene))bis(dibenzo[c,e][1,2]oxaphosphinine 6-oxide) 5c and 6,6'-((oxybis(4,1-phenylene))bis(1-(thiophen-2-yl)ethane-2,1-diyl))bis(dibenzo[c,e][1,2]oxaphosphinine 6-oxide) 5d. Among them, flame retardants 5a and 5d were synthesized for the first time. DOPO derivatives were combined with functionalized ammonium polyphosphate using polyethyleneimine (PEI-APP) as flame retardant systems for epoxy composites. The combination of compound 5a and PEI-APP gave the materials with the best flame retardancy. 6wt% of PEI-APP/6% of 5a promoted the composite material to V-0 rating in UL-94 vertical burning test and the limiting oxygen index reached 28.9%. The impact of flame retardants towards the mechanical and physical properties of epoxy resin was also evaluated. The combination of 5a with PEI-APP showed the least decrease in mechanical strength of epoxy composite.

Hybrids of selective COX-2 inhibitors and active derivatives of edaravone as COX-2 selective NSAIDs with free radical scavenging activity: Design, synthesis and biological activities

Novel hybrids of selective COX-2 inhibitors (coxibs) and active derivatives of free radical scavenger edaravone were designed to overcome the risk of cardiovascular events and stroke increased by NSAIDs (nonsteroidal anti-inflammatory drugs) in this study. All the hybrids were assayed for the COX-2 inhibitory and DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging activities in vitro. Finally, we found a series of hybrids with good inhibitory activity and selectivity of COX-2 and excellent free radical scavenging activity in vitro. The most promising compound 6a (WYZ90) exhibited very potent COX-2 inhibitory activity (COX-2, IC50 = 75 nM), weak COX-1 inhibitory activity (COX-1, IC50 = 5734 nM), better free radical scavenging activity (DPPH, IC50 = 19.9 μM) than edaravone, moderate drug-likeness and ADME properties in silico, acceptable pharmacokinetic properties (T1/2 = 4.16 h, 10 mg/kg, o.p.) and oral bioavailability (F% = 36.03 %) in mice. In addition, compound WYZ90 showed similar analgesic activity to the selective COX-2 inhibitor celecoxib in acetic acid-induced mice and better antioxidant activity in Fe2+-induced lipid peroxidation in mouse liver tissue homogenate than edaravone. In conclusion, this study provided a novel class of coxibs containing edaravone moiety as COX-2 selective NSAIDs with free radical scavenging activity and the candidate compound WYZ90 showed not only similar selective COX-2 inhibitory and analgesic activity to celecoxib but also better free radical scavenging and antioxidant activity than edaravone.

Synthesis of Cinnamoylhydroxamic Acid Derivatives Bearing Sulfonamide, Amide Bonds as Connecting Unit Targeting Histone Deacetylases

Based on the strong activity of belinostat, the study synthesized of some cinnamoylhydroxamic acid derivatives with the aim of creating new compounds that have the potential to selectively inhibit HDAC to contribute to cancer treatment. N-hydroxycinnamamide serves as both ZBG and the linker group. The derivatives orient to the HDAC2 and HDAC8 enzymes by molecular docking. Compound 9a (bearing sulfonamide) exhibited as the most potential candidate to inhibit the function of HDAC2 enzyme.

Study on Design, Synthesis and Herbicidal Activity of Novel 6-Indazolyl-2-picolinic Acids.

Thirty-eight new 4-amino-3,5-dicholo-6-(1H-indazolyl)-2-picolinic acids and 4-amino-3,5-dicholo-6-(2H-indazolyl)-2-picolinic acids were designed by scaffold hopping and synthesized to discover potential herbicidal molecules. All the new compounds were tested to determine their inhibitory activities against Arabidopsis thaliana and the root growth of five weeds. In general, the synthesized compounds exhibited excellent inhibition properties and showed good inhibitory effects on weed root growth. In particular, compound 5a showed significantly greater root inhibitory activity than picloram in Brassica napus and Abutilon theophrasti Medicus at the concentration of 10 µM. The majority of compounds exhibited a 100% post-emergence herbicidal effect at 250 g/ha against Amaranthus retroflexus and Chenopodium album. We also found that 6-indazolyl-2-picolinic acids could induce the up-regulation of auxin genes ACS7 and NCED3, while auxin influx, efflux and auxin response factor were down-regulated, indicating that 6-indazolyl-2-picolinic acids promoted ethylene release and ABA production to cause plant death in a short period, which is different in mode from other picolinic acids.

Structure-guided design of potent JAK1-selective inhibitors based on 4-amino-7H-pyrrolo[2,3-d]pyrimidine with anti-inflammatory efficacy.

In a continuous effort to develop Janus kinase 1 (JAK1)-selective inhibitors, a novel series of 4-amino-7H-pyrrolo[2,3-d]pyrimidine derivatives bearing the piperidinyl fragment were designed and synthesized according to a combination strategy. Through enzymatic assessments, the superior compound 12a with an IC50 value of 12.6 nM against JAK1 was identified and a 10.7-fold selectivity index over JAK2 was achieved. It was indicated that 12a displayed considerable effect in inhibiting the pro-inflammatory NO generated from lipopolysaccharide (LPS)-induced RAW264.7 macrophages, while on normal RAW264.7 cells, 12a exerted a weak cytotoxicity effect (IC50 = 143.3 μM). Furthermore, H&E stain assay demonstrated the conspicuous capacity of 12a to suppress CCl4-induced hepatic fibrosis levels in a dose-dependent manner in vivo. The binding model of 12a ideally reflects the excellent activity of JAK1 over the homologous kinase JAK2. Overall, 12a, a JAK1-selective inhibitor, exhibited potential for liver fibrosis and inflammatory diseases.

Fluorescence and magnetic resonance imaging of ONL-93 cells in a rat model of ischemic

ObjectivesThe current methods for detecting myelin changes in ischemic stroke are indirect and cannot accurately reflect their status. This study aimed to develop a novel fluorescent-magnetic resonance dual-modal molecular imaging probe for direct imaging of myelin. MethodsCompounds 7a and 7b were synthesized by linking the MeDAS group and Gadolinium (III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. Compound 7a was selected for characterization and further study. Cell uptake, cytotoxicity, and magnetic resonance imaging scans were performed on cells. In vitro experiments on frozen brain sections from 7-day-old, 8-week-old, and ischemic stroke rats were compared with commercially available Luxol Fast Blue staining. After HPLC and MR scanning, brain tissue was soaked in 7a and scanned using T1WI and T1maps sequences. ResultsSpectrophotometer results showed that compounds 7a and 7b had fluorescent properties. MR scans indicated that the compounds had contrast agent properties. Cells could uptake 7a and exhibited high signals in imaging scans. Compound 7a brain tissue staining showed more fluorescence in myelin-rich regions and identified injury sites in ischemic stroke rats. MR scanning of brain sections provided clear myelin contrast. ConclusionA novel fluorescent-magnetic resonance dual-modal molecular imaging probe for direct imaging of myelin was successfully developed and tested in rats with ischemic stroke. These findings provide new insights for the clinical diagnosis of demyelinating diseases.