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IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC)2-Fe2+-NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo. [ABSTRACT FROM AUTHOR]

The dose proportionality and bioavailability of the potential anti-inflammatory and neuroprotective JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) were evaluated by comparing pharmacokinetic parameters after single oral (25, 50 and 100 mg/kg) and intravenous (1 mg/kg) IQ-1 administration in rats. IQ-1 and its major metabolite ketone 11H-indeno[1,2-b]quinoxalin-11-one (IQ-18) were isolated from plasma samples by liquid–liquid extraction. IQ-1 (E-isomer) and IQ-18 were simultaneously quantified in plasma by the validated method of liquid chromatography with triple quadrupole mass spectrometry (HPLC–MS/MS). The absolute bioavailability of IQ-1 was < 1.5%. Cmax values were 24.72 ± 4.30, 25.66 ± 7.11 and 37.61 ± 3.53 ng/mL after single oral administration of IQ-1 at doses of 25, 50 and 100 mg/kg, respectively. IQ-1 exhibited dose proportionality at 50–100 mg/kg dose levels, whereas its pharmacokinetics was not dose proportional over the range of 25–50 mg/kg. IQ-18 demonstrated the invariance of the dose-normalized Cmax. In this study we systematically elucidated the absorption characteristics of IQ-1 in rat gastrointestinal tract and provided better understanding of IQ-1 pharmacology for the future development of a new formulations and therapeutic optimisation. [ABSTRACT FROM AUTHOR]

11H-Indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and tryptanthrin-6-oxime are potent c-Jun N-terminal kinase 3 (JNK-3) inhibitors demonstrating neuroprotective, anti-inflammatory and anti-arthritic activity. However, the stereochemical configuration of the oxime carbon–nitrogen double bond (E- or Z-) in these compounds was so far unknown. In this contribution, we report the results of the determination of the double bond configuration in the solid state by single crystal X-ray diffraction and in solution by 1D and 2D NMR techniques and DFT calculations. It was found that both in the solid state and in solution, IQ-1 adopts the E-configuration stabilized by intermolecular hydrogen bonds, in contrast to previously assumed Z-configuration that could be stabilized only by an intramolecular hydrogen bond. [ABSTRACT FROM AUTHOR]

Indolo[2,1-b]quinazolin-6,12-dione (tryptanthrin) derivatives present important types of nitrogen-containing heterocyclic compounds which are useful intermediate products in organic synthesis and have potential pharmaceutical applications. The new ethyl 5-oxo-5-(((12-oxoindolo[2,1-b]quinazolin-6(12H)-ylidene)amino)oxy)pentanoate (Compound 2) was synthesized. Compound 2 is the first example of a tryptanthrin derivative containing a dicarboxylic acid residue in the side chain. The Z,E-isomerism of Compound 2 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, Compound 2 is potentially highly bioavailable and has the prospective to be used as the main component for the development of anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

11H-Indeno[1,2-b]quinoxaline derivatives present an important type of nitrogen-containing heterocyclic compound that are useful intermediate products in organic synthesis and have potential pharmaceutical applications. A new 11H-indeno[1,2-b]quinoxalin-11-one-2-(4-ethylbenzylidene)hydrazone (compound 3) was synthesized. Compound 3 is the first example of an azine derivative based on the 11H-indeno[1,2-b]quinoxaline system. The Z,E-isomerism of compound 3 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, compound 3 is potentially highly bioavailable and has potential to be used for the treatment of neuroinflammation and ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]

c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]