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Background The transcription factor Nuclear factor erythroid-2-related factor 2 (NRF2) and its principal repressive regulator, Kelch-like ECH-associated protein 1 (KEAP1), are perilous in the regulation of inflammation, as well as maintenance of homeostasis. Thus, NRF2 activation is involved in cytoprotection against many inflammatory disorders. N′-Nicotinoylquinoxaline-2-carbohdyrazide (NQC) was structurally designed by the combination of important pharmacophoric features of bioactive compounds reported in the literature. Methods NQC was synthesised and characterised using spectroscopic techniques. The compound was tested for its anti-inflammatory effect using Lipopolysaccharide from Escherichia coli (LPSEc) induced inflammation in mouse macrophages (RAW 264.7 cells). The effect of NQC on inflammatory cytokines was measured using enzyme-linked immune sorbent assay (ELISA). The Nrf2 activity of the compound NQC was determined using ‘Keap1:Nrf2 Inhibitor Screening Assay Kit’. To obtain the insights on NQC’s activity on Nrf2, molecular docking studies were performed using Schrödinger suite. The metabolic stability of NQC was determined using mouse, rat and human microsomes. Results NQC was found to be non-toxic at the dose of 50 µM on RAW 264.7 cells. NQC showed potent anti-inflammatory effect in an in vitro model of LPSEc stimulated murine macrophages (RAW 264.7 cells) with an IC50 value 26.13 ± 1.17 µM. NQC dose-dependently down-regulated the pro-inflammatory cytokines [interleukin (IL)-1β (13.27 ± 2.37 μM), IL-6 (10.13 ± 0.58 μM) and tumor necrosis factor (TNF)-α] (14.41 ± 1.83 μM); and inflammatory mediator, prostaglandin E2 (PGE2) with IC50 values, 15.23 ± 0.91 µM. Molecular docking studies confirmed the favourable binding of NQC at Kelch domain of Keap-1. It disrupts the Nrf2 interaction with kelch domain of keap 1 and its IC50 value was 4.21 ± 0.89 µM. The metabolic stability studies of NQC in human, rat and mouse liver microsomes revealed that it is quite stable with half-life values; 63.30 ± 1.73, 52.23 ± 0.81, 24.55 ± 1.13 min; microsomal intrinsic clearance values; 1.14 ± 0.31, 1.39 ± 0.87 and 2.96 ± 0.34 µL/min/g liver; respectively. It is observed that rat has comparable metabolic profile with human, thus, rat could be used as an in vivo model for prediction of pharmacokinetics and metabolism profiles of NQC in human. Conclusion NQC is a new class of NRF2 activator with potent in vitro anti-inflammatory activity and good metabolic stability.

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A simple and elegant method for the synthesis of 1,5-benzothiazepines has been developed using di-cationic liquid as a solvent cum catalyst by the reaction of o-aminothiophenol with a variety of chalcones under mild reaction conditions. Furthermore the reusability of the catalyst has also been studied for three cycles. All the reactions are proposed to proceed through a 1,4-conjugate Michael addition followed by a cyclo-condensation reaction. [21][22][23]. In addition to this, the special properties of the ionic liquids have influenced the rate of chemical reactions such as elimination reactions where, the rate of the reaction in ionic liquids was observed to be faster than those carried out in conventional organic solvents [24]. Notably, multifunctional group dicationic ionic liquids have been reported to have a greater range of physical properties than traditional and singly charged ionic liquids. They are often more thermally stable, less volatility and are more flexible in tuning their physicochemical virtues [25,26]. Herein, we report an efficient synthesis of various 1,5-benzothiazepines using dicationic liquids as a catalyst and as well as solvent. EXPERIMENTALGeneral procedure: A mixture of o-aminothiophenol (1.2 mmol)/o-phenylenediamine (1 mmol), chalcone (1.0 mmol) and IL-C (0.2 mmol, 0.1 g per mmol of chalcone) was stirred at 80 °C for 80 min under nitrogen atmosphere. After completion of the reaction, which was monitored by TLC, the reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (3 × 25 mL). The combined organic layer was separated and dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by crystallization in ethanol to afford the pure solid 1,5-benzothiazepines. The water present in the aqueous layer was subjected for distillation and the left over residue contains the pure ionic liquid, which could be recycled.

A variety of flavanones and azaflavanones have been synthesised from chalcones, catalysed by 30 mol% solid support proline terminal peptide, which is mildly efficient with high conversions yields and could be recycled up to three times without significant loss in its activity.Keywords: , Solid Support Peptide Catalyst, Reusable Catalyst, Cyclisation, Flavanones