N,N-Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin-6 Levels in Cells through Nuclear Factor-κB Regulation.

The arylsulfonamides were synthesized from aryl sulfonyl chloride and aromatic amines in dichloromethane in the presence of pyridine. The aryne chemistry was used to prepare diarylsulfonamide from arylsulfonamides and O-silylaryl triflate with CsF in acetonitrile at room temperature for 30 min. The synthesized compounds were evaluated for cytotoxicity followed by the cytokine/inflammatory marker's inhibition capability and its mechanism of action in RAW-264.7 cells. Elevated interleukin-6 (IL-6) levels have been reported in inflammatory conditions and inflammation-associated disorders. Hence, reducing the IL-6 levels in inflammatory conditions can serve as an attractive therapeutic target in dealing the inflammation. Among 42 compounds, seven compounds showed significant inhibition of IL-6 levels in lipopolysaccharide (LPS) challenged RAW-264.7 cells at 12.5 µM concentration. Further, investigation revealed that the IC50 value of these compounds for reducing IL-6 levels was found to be in the range of 2.6 to 9.7 µM. The promising compounds 5y (IC50 of 2.6 µM) and 5n (IC50 of 4.1 µM) along with other derivatives fulfil drug-likeness parameters laid down by Lipinski's rule of five. Further, RT-qPCR and Western-blot analysis revealed that treatment with 5n significantly reduced the expression of pro-inflammatory, inflammatory and macrophage marker's expression (IL-1ß, CCL2, COX2 and CD68) compared to LPS control. The mechanistic evaluation showed that 5n exhibited anti-inflammatory properties by modulating the nuclear factor-κB (NF-κB) activation. The identified compound can be a promising candidate for further discovery efforts to generate a preclinical candidate effective in inflammation.

Stress-responsive gene regulation conferring salinity tolerance in wheat inoculated with ACC deaminase producing facultative methylotrophic actinobacterium.

Microbes enhance crop resilience to abiotic stresses, aiding agricultural sustainability amid rising global land salinity. While microbes have proven effective via seed priming, soil amendments, and foliar sprays in diverse crops, their mechanisms remain less explored. This study explores the utilization of ACC deaminase-producing Nocardioides sp. to enhance wheat growth in saline environments and the molecular mechanisms underlying Nocardioides sp.-mediated salinity tolerance in wheat. The Nocardioides sp. inoculated seeds were grown under four salinity regimes viz., 0 dS m-1, 5 dS m-1, 10 dS m-1, and 15 dS m-1, and vegetative growth parameters including shoot-root length, germination percentage, seedling vigor index, total biomass, and shoot-root ratio were recorded. The Nocardioides inoculated wheat plants performed well under saline conditions compared to uninoculated plants and exhibited lower shoot:root (S:R) ratio (1.52 ± 0.14 for treated plants against 1.84 ± 0.08 for untreated plants) at salinity level of 15 dS m-1 and also showed improved biomass at 5 dS m-1 and 10 dS m-1. Furthermore, the inoculated plants also exhibited higher protein content viz., 22.13 mg g-1, 22.10 mg g-1, 22.63 mg g-1, and 23.62 mg g-1 fresh weight, respectively, at 0 dS m-1, 5 dS m-1, 10 dS m-1, and 15 dS m-1. The mechanisms were studied in terms of catalase, peroxidase, superoxide dismutase, and ascorbate peroxidase activity, free radical scavenging potential, in-situ localization of H2O2 and superoxide ions, and DNA damage. The inoculated seedlings maintained higher enzymatic and non-enzymatic antioxidant potential, which corroborated with reduced H2O2 and superoxide localization within the tissue. The gene expression profiles of 18 stress-related genes involving abscisic acid signaling, salt overly sensitive (SOS response), ion transporters, stress-related transcription factors, and antioxidant enzymes were also analyzed. Higher levels of stress-responsive gene transcripts, for instance, TaABARE (~+7- and +10-fold at 10 dS m-1 and 15 dS m-1); TaHAk1 and hkt1 (~+4- and +8-fold at 15 dS m-1); antioxidant enzymes CAT, MnSOD, POD, APX, GPX, and GR (~+4, +3, +5, +4, +9, and +8 folds and), indicated actively elevated combat mechanisms in inoculated seedlings. Our findings emphasize Nocardioides sp.-mediated wheat salinity tolerance via ABA-dependent cascade and salt-responsive ion transport system. This urges additional study of methylotrophic microbes to enhance crop abiotic stress resilience.

Iron mediated reductive cyclization/oxidation for the generation of chemically diverse scaffolds: An approach in drug discovery.

Chemically diverse scaffolds represent a main source of biologically important starting points in drug discovery. Herein, we report the development of such diverse scaffolds from nitroarene/ nitro(hetero)arenes using a key synthetic strategy. In a pilot-scale study, the synthesis of 10 diverse scaffolds was achieved. The 1,7-phenanthroline, thiazolo[5,4-f]quinoline, 2,3-dihydro-1H-pyrrolo[2,3-g]quinoline, pyrrolo[3,2-f]quinoline, 1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one, [1,2,5]oxadiazolo[3,4-h]quinoline, 7H-pyrido[2,3-c]carbazole, 3H-pyrazolo[4,3-f]quinoline, pyrido[3,2-f]quinoxaline were obtained from nitro hetero arenes in ethanol using iron-acetic acid treatment followed by reaction under oxygen atmosphere. This diverse library is compliant with the rule of five for drug-likeness. The mapping of chemical space represented by these scaffolds revealed a significant contribution to the underrepresented chemical diversity. Crucial to the development of this approach was the mapping of biological space covered by these scaffolds which revealed neurotropic and prophylactic anti-inflammatory activities. In vitro, neuro-biological assays revealed that compounds 14a and 15a showed excellent neurotropic potential and neurite growth compared to controls. Further, anti-inflammatory assays (in vitro and in vivo models) exhibited that Compound 16 showed significant anti-inflammatory activity by attenuating the LPS-induced TNF-α and CD68 levels by modulating the NFkB pathway. In addition, treatment with compound 16 significantly ameliorated the LPS-induced sepsis conditions, and pathological abnormalities (in lung and liver tissues) and improved the survival of the rats compared to LPS control. Owing to their chemical diversity along with bioactivities, it is envisaged that new quality pre-clinical candidates will be generated in the above therapeutic areas using identified leads.

Methylene-Tethered Arylsulfonation and Benzotriazolation of Aryl/Heteroaryl C-H Bonds with DMSO as a One-Carbon Surrogate.

The Selectfluor-mediated approach toward the synthesis of methylene-tethered arylsulfonation and benzotriazolation of imidazopyridines has been described. The reaction involves imidazopyridine, aryl sulfinate, or benzotriazole and dimethyl sulfoxide (DMSO) in the presence of Selectfluor, where DMSO acts as a one-carbon synthon. The protocol has been extended to the methylene-tethered arylsulfonation and benzotriazolation of ß-naphthols. The mechanistic insights show that the intermediate 3-((methylthio)methyl)-2-phenylimidazo[1,2-a]pyridine is generated from imidazopyridine, DMSO, and Selectfluor. The nucleophilic displacement by the aryl sulfinate salt or benzotriazole on the intermediate afforded the product.

3-Aryl-substituted imidazo[1,2-a]pyridines as antituberculosis agents.

Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 µg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.

Pyro-phototronic nanogenerator based on flexible 2D ZnO/graphene heterojunction and its application in self-powered near infrared photodetector and active analog frequency modulation.

Even though 2D ZnO has been utilized for enhanced self-powered sensing by strain modulation due to its piezoelectric property, study on utilizing the pyroelectric property of ZnO remains unexplored. The piezoelectric property of 2D ZnO works on mechanical strain, which disrupts the structure of ZnO leading to the failure of the device. For a pyroelectric nanogenerator, the temperature difference can be triggered by an external light source, which does not disrupt the ZnO structure and also avoids the need for physical bending/pressing, as in the case of a piezoelectric nanogenerator. This work represents the first demonstration of the fabrication of a flexible 2D ZnO/Gr pyro-phototronic diode where the pyro-potential generated in the 2D ZnO due to the near infrared (NIR) illumination adds to or subtracts from the built-in electric field of the heterojunction and modulates the depletion region of the heterojunction thereby enabling bias-free operation. Furthermore, the variation in the depletion width of the heterojunction was utilized as a variable capacitor in the frequency modulator, wherein, with the increasing intensity, the frequency of oscillations increased from 9.8 to 10.42 MHz. The work presented provides an alternative approach for a self-powered NIR photodetector and the utilization of the same at circuit level, having potential applications in the fields of optothermal detection, electronic tuning circuits, etc.