The Effect of Basic Ligands and Alkenes on the Regioselectivity of C-H Additions of Tertiary Amines to Alkenes.

Highly regioselective C-H alkylation reactions of tertiary anilines and tertiary alkyl amines with simple alkenes have been achieved by the use of imidazolin-2-iminato scandium alkyl complexes. This protocol provided an efficient and atom-economical route to structurally diverse tertiary amine derivatives. The basic ligand, a coordinating THF in the catalyst and the substitution of alkene substrates were found to switch the regioselectivity of the C-H alkylation reactions of tertiary anilines presumably due to the generation of different types of catalytically active species or the formation of relatively stable intermediates. On the basis of the deuterium labeling experiments and KIE experiments, possible catalytical cycles were provided to understand the reaction mechanism as well as the regioselectivity.

Taxonomic and functional changes in wheat rhizosphere microbiome caused by imidazoline-based herbicide and genetic modification.

Genetically modified (GM) crop cultivation has received a lot of attention in recent years due to the substantial public debate. Consequently, an in-depth investigation of excessively used GM herbicide-tolerant crops is a vital step for the biosafety of genetically modified plants. Several studies have been conducted to study the impact of transgenic GM crops on soil microbial composition; however, research into the effects of non-transgenic GM crops is inadequate. In the current work, high-throughput sequencing was used to evaluate the impact of the acetolactate synthase (ALS)-mutant (WK170B), its control (YN19B), and the imazamox (IM) herbicide on the wheat rhizobiome. Under normal growth conditions, our work revealed a minimal impact of ALS-mutant WK170B on the rhizosphere microbiome compared to the control YN10B, except for some cyanobacterial microorganisms that showed a significant increase in abundance. This suggests that the gene mutation could potentially have a beneficial impact on the bacterial communities present in the rhizosphere. Following IM exposure, taxonomic analysis revealed a significant reduction in the relative abundance of Ralstonia pickettii and an unidentified member of the genus Ancylothrix 8 PC. Analyses of both alpha and beta diversity revealed a statistically significant increase in both microbial richness and species diversity. IM-induced relative abundance modulation was also evident through Linear discriminant analysis Effect Size (LEfSe), MetaStat, and heatmap analyses. The SIMPER analysis revealed that the microbial taxa Massilia, Limnobacter, Hydrogenophaga, Ralstonia, Nitrospira, and Ramlibacter exhibited the highest vulnerability to IM exposure. The functional attributes analysis revealed that the relative abundance of genes associated with the extracellular matrix-receptor interaction, which is responsible for structural support and stress response, increased significantly following IM exposure. Collectively, our study identifies key microbial taxa in the wheat rhizobiome that are sensitive to IM herbicides and provides a foundation for assessing the environmental risks associated with IM herbicide use.

Synthesis of Antiprotozoal 2-(4-Alkyloxyphenyl)-Imidazolines and Imidazoles and Their Evaluation on Leishmania mexicana and Trypanosoma cruzi.

Twenty 2-(4-alkyloxyphenyl)-imidazolines and 2-(4-alkyloxyphenyl)-imidazoles were synthesized, with the former being synthesized in two steps by using MW and ultrasonication energy, resulting in good to excellent yields. Imidazoles were obtained in moderate yields by oxidizing imidazolines with MnO2 and MW energy. In response to the urgent need to treat neglected tropical diseases, a set of 2-(4-alkyloxyphenyl)- imidazolines and imidazoles was tested in vitro on Leishmania mexicana and Trypanosoma cruzi. The leishmanicidal activity of ten compounds was evaluated, showing an IC50 < 10 µg/mL. Among these compounds, 27-31 were the most active, with IC50 values < 1 µg/mL (similar to the reference drugs). In the evaluation on epimastigotes of T. cruzi, only 30 and 36 reached an IC50 < 1 µg/mL, showing better inhibition than both reference drugs. However, compounds 29, 33, and 35 also demonstrated attractive trypanocidal activities, with IC50 values < 10 µg/mL, similar to the values for benznidazole and nifurtimox.

Reactive astrogliosis: A friend or foe in the pathogenesis of Alzheimer's disease.

Astrocytes are highly efficient homeostatic glial cells playing a crucial role in optimal brain functioning and homeostasis. Astrocytes respond to changes in brain homoeostasis following central nervous system (CNS) injury/diseased state by a specific defence mechanism called reactive astrogliosis. Recent studies have implicated and placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. The AD biomarker field is evolving rapidly with new findings providing strong evidence which supports the notion that a reactive astrogliosis is an early event in the time course of AD progression which may precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in vitro postmortem brain imaging studies demonstrated 'a first and second wave' of reactive astrogliosis in AD with distinct close-loop relationships with other pathological biomarkers at different stages of the disease. At the end stages, reactive astrocytes are found to be associated, or in proximity, with amyloid plaque and tau pathological deposits in postmortem AD brains. Several new PET-tracers, which are being in pipeline and validated at a very fast pace for mapping and visualising reactive astrogliosis in the brain, will provide further invaluable mechanistic insights into AD and other non-AD dementia pathologies. The complementary roles of microglia and astrocyte activation in AD progression, along with the clinical value of new fluid astrocytes biomarkers in the context of existing biomarkers, are the latest avenue that needs further exploration.

Investigation on the Anticancer and Antibacterial Mechanism of Thiazoline/Imidazoline Derived Palladium(II) Complexes.

Biological activities of a series of palladium(II) complexes (M1-M9) bearing N∩ N, N∩ S, and N∩ O chelating ligands are reported. The palladium complexes were tested for their cytotoxic properties against human cervical cancer (HeLa) cells and antibacterial activity against Gm+ve and Gm-ve bacteria. Among the palladium complexes studied (M1-M9), the complex M5, M8, and M9 were found to be more effective in inhibiting the proliferation of HeLa cells. Hence, these complexes were further investigated for their potential role in cellular damage and apoptosis. DCFDA staining, Rhodamine 123 staining and DNA cleavage assay revealed that complex M5, M8 and M9 induced apoptotic cell death in HeLa cells through ROS generation, DNA damage and mitochondrial depolarization. Computational and titration studies also indicated strong electrostatic interaction with DNA groove. Most of the complexes exhibited good antibacterial activity against both Gm+ve and Gm-ve bacteria. The antibacterial activity of the compounds could not be correlated with their anticancer activity indicating a differential mechanism at their effective concentrations. The detailed study on the antibacterial mechanism of the most potent complex M7 revealed that it exerted its antibacterial activity by inhibiting the function of FtsZ and perturbing the localization of the Z-ring at the mid cell.

Novel synthesis of 11 C-labeled imidazolines via Pd(0)-mediated 11 C-carbomethoxylation using [11 C]CO and arylborons.

A labeling technique was developed for the imidazoline I2 receptor ligand 2-(3-fluoro-tolyl)-4, 5-dihydro-1H-imidazole (FTIMD) using Pd(0)-mediated 11 C-carbomethoxylation with [11 C]CO, followed by imidazoline ring formation with ethylenediamine-trimethylaluminium (EDA-AlMe3 ). To achieve this, [11 C]CO was passed through a methanol (MeOH) solution containing 3-fluoro-4-methylphenylboronic acid (1), palladium (II) acetate (Pd [OAc]2 ), triphenylphosphine (PPh3 ), and p-benzoquinone (PBQ). The mixture was then heated at 65°C for 5 min. EDA was introduced into the reaction mixture, and MeOH was completely evaporated at temperatures exceeding 100°C. The dried reaction mixture was combined with an EDA-AlMe (1:1) toluene solution and heated at 145°C for 10 min. Portions of the reaction mixture were analyzed through high-performance liquid chromatography, resulting in [11 C]FTIMD with 26% (n = 2) decay-corrected radiochemical yield (RCY). This method could be utilized for various arylborons to produce [2-11 C]imidazolines 4a-h with RCYs ranging from low to moderate. Notably, [2-11 C]benazoline was obtained with a moderate RCY of 65%. The proposed technique serves as an alternative to the Grignard method, which uses [11 C]CO to generate a [2-11 C]-labeled imidazoline ring.

Imidazoline-I2 PET Tracers in Neuroimaging.

Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such as PET imaging tools that are specific for the cell type(s) of interest. This review concentrates on the recent advances in the development of Imidazoline2 binding site (I2BS) PET tracers, which are purported to target astrocytes, and hence could represent key clinical imaging tools for targeting astrocytes in neurodegenerative disease. Five PET tracers for the I2BS are described in this review, with only one (11C-BU99008) being currently validated to GMP for clinical use, and data reported from healthy volunteers, Alzheimer's disease patients, and Parkinson's disease patients. The clinical data utilising 11C-BU99008 have revealed the potential early involvement of astrogliosis in neurodegeneration that might precede the activation of microglia, which, if confirmed, could provide a vital new means for potentially targeting neurodegeneration earlier in the disease course.

Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands.

The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

A pH-Controlled Solid Inhibitor Based on PAM Hydrogel for Steel Corrosion Protection in Wide Range pH NaCl Medium.

To provide carbon steel a long-term corrosion protection effect in NaCl solutions with different pH values, based on poly-acrylamide (PAM) and oleate imidazoline (OIM), a solid corrosion inhibitor with the properties of pH-controlled release was synthesized. SEM, FTIR and TGA results indicated that the OIM inhibitors were successfully loaded into PAM hydrogel with a high OIM encapsulation content (39.64 wt.%). The OIM release behavior from the hydrogel structure has two stages, quick release and sustained release. The pH of solutions could affect the initial release kinetics of OIM inhibitors and the diffusion path in the hydrogel structure. Weight loss measurement of L80 steel in different pH solutions with OIM@PAM proved the inhibitor responsive release mechanism and anticorrosion performance. The inhibition efficiency of OIM@PAM can maintain over 80% after long-term immersion in a harsh corrosive environment (pH 3), which is much higher than the inhibition efficiency of OIM@PAM in a moderate corrosive solution.

I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice.

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer's disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-ß (Aß) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aß levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aß-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06.

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I2-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer's disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson's disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I2-IR as a fresh approach for the therapy of ND.

Design, synthesis and anti-hypoxia activity of HPN derivatives containing lipophilic long chains.

OBJECTIVE: To design and synthesize long-chain substituted 2-[(4'-hydroxyethoxy) phenyl]-4,4,5,5-tetramethyl-2-imidazoline-1-oxyl 3-oxide (HPN) derivatives with enhanced anti-hypoxic activity. METHODS: HPN derivatives 1, 3, 5 containing lipophilic long chains were synthesized via the alkylation of HPN with 6-bromohexan-1-ol, ethyl 6-bromohexanoate or 6-bromohexane, respectively using acetonitrile as the solvent and K 2CO 3 as the acid-binding agent at 60 ℃. Derivative 2 was synthesized via hydrolysis reactions of derivative 1 in the NaOH/CH 3OH/H 2O system. Using dichloromethane as the solvent and N, N'-diisopropylcarbodiimide as the dehydrating agent, HPN underwent esterification with hexanoic acid to obtain derivative 4. The structures of derivatives 1-5 were characterized by infrared spectroscopy, electron paramagnetic resonance and high resolution mass spectrometry. The purities of derivatives were detected by high performance liquid chromatography, and the lipid solubilities of derivatives were evaluated by calculating the oil-water partition coefficients (log P). Anti-hypoxia activities of HPN and its long-chain lipophilic derivatives 1-5 were evaluated using normobaric hypoxia test and acute decompression hypoxia test. RESULTS: The structures of the derivatives were confirmed by infrared spectroscopy, electron paramagnetic resonance and high resolution mass spectroscopy. The yields of target derivatives were all above 92%, and the purities were all above 96%. The log P values of derivatives 1-5 were 2.78, 2.00, 2.04, 2.88 and 3.10, which were higher than that of HPN (0.97). Derivatives 1-5 significantly prolonged the survival time of mice at the dose of 0.3 mmol/kg in normobaric hypoxic test and reduced the mortality rate of acute decompression hypoxic mice to 60%, 70%, 60%, 70% and 40%, respectively. CONCLUSIONS: The synthesis of derivatives 1-5 is convenient, and the yield is high. The synthesized derivatives especially derivative 5 show anti-hypoxic activity similar to or better than HPN at lower doses.

Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications.

The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently affected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guidance on their use. This review discusses the etiology of hypertension, and more specifically the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the effects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline receptor agonists.

Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors.

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.

Protein kinase C-mediated calcium signaling as the basis for cardiomyocyte plasticity.

Protein kinase C is the superfamily of intracellular effector molecules which control crucial cellular functions. Here, we for the first time did the percentage estimation of all known PKC and PKC-related isozymes at the individual cadiomyocyte level. Broad spectrum of PKC transcripts is expressed in the left ventricular myocytes. In addition to the well-known 'heart-specific' PKCα, cardiomyocytes have the high expression levels of PKCN1, PKCδ, PKCD2, PKCε. In general, we detected all PKC isoforms excluding PKCη. In cardiomyocytes PKC activity tonically regulates voltage-gated Ca2+-currents, intracellular Ca2+ level and nitric oxide (NO) production. Imidazoline receptor of the first type (I1R)-mediated induction of the PKC activity positively modulates Ca2+ release through ryanodine receptor (RyR), increasing the Ca2+ leakage in the cytosol. In cardiomyocytes with the Ca2+-overloaded regions of > 9-10 µm size, the local PKC-induced Ca2+ signaling is transformed to global accompanied by spontaneous Ca2+ waves propagation across the entire cell perimeter. Such switching of Ca2+ signaling in cardiac cells can be important for the development of several cardiovascular pathologies and/or myocardial plasticity at the cardiomyocyte level.

Synthesis and chiral separation of atropisomers of 4,5-Di methyl ∆4 N-phenyl N-aryl imidazoline-2-thione derivatives.

Synthesis of three chiral 4,5-Di methyl ∆4 N-phenyl N-aryl imidazole-2-thione derivatives was obtained by the condensation reaction of thiourea derivatives with α-hydroxy ketone. The structure of these compounds has been characterized by using spectroscopic methods (UV, IR, 1 H NMR, and 13 C NMR). The 4,5-Di methyl ∆4 N-phenyl N-aryl imidazole-2-thiones display a chiral axis around the N-C bond linking between the nitrogen of the heterocyclic framework and the carbon of the aryl group. Screening on chiral analysis of the atropisomers of these derivatives was performed by high-performance liquid chromatography method on seven chiral selectors based on polysaccharides consisting of amylose and cellulose, namely, Chiralpak®AD, Chiralcel® OD, Chiralcel® OD-H, Chiralcel® OJ, Chiralcel® OD-3R, Chiralcel® OZ-3, and Chiralpak® AS-3R. The impact of ortho-substituent in the resolution of 4,5-Di methyl ∆4 N-phenyl N-aryl imidazole-2-thione derivatives was also studied in this work.

Solid-Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond.

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).

Exploiting the Chiral Ligands of Bis(imidazolinyl)- and Bis(oxazolinyl)thiophenes-Synthesis and Application in Cu-Catalyzed Friedel-Crafts Asymmetric Alkylation.

Five new C2-symmetric chiral ligands of 2,5-bis(imidazolinyl)thiophene (L1-L3) and 2,5-bis(oxazolinyl)thiophene (L4 and L5) were synthesized from thiophene-2,5-dicarboxylic acid (1) with enantiopure amino alcohols (4a-c) in excellent optical purity and chemical yield. The utility of these new chiral ligands for Friedel-Crafts asymmetric alkylation was explored. Subsequently, the optimized tridentate ligand L5 and Cu(OTf)2 catalyst (15 mol%) in toluene for 48 h promoted Friedel-Crafts asymmetric alkylation in moderate to good yields (up to 76%) and with good enantioselectivity (up to 81% ee). The bis(oxazolinyl)thiophene ligands were more potent than bis(imidazolinyl)thiophene analogues for the asymmetric induction of the Friedel-Crafts asymmetric alkylation.

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals.

Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at a-, b-, or g-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9'(10H,10H')-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores.

Stable Bicyclic Functionalized Nitroxides: The Synthesis of Derivatives of Aza-nortropinone-5-Methyl-3-oxo-6,8-diazabicyclo[3.2.1]-6-octene 8-oxyls.

In recent decades, bicyclic nitroxyl radicals have caught chemists' attention as selective catalysts for the oxidation of alcohols and amines and as additives and mediators in directed C-H oxidative transformations. In this regard, the design and development of synthetic approaches to new functional bicyclic nitroxides is a relevant and important issue. It has been reported that imidazo[1,2-b]isoxazoles formed during the condensation of acetylacetone with 2-hydroxyaminooximes having a secondary hydroxyamino group are recyclized under mild basic catalyzed conditions to 8-hydroxy-5-methyl-3-oxo-6,8-diazabicyclo[3.2.1]-6-octenes. The latter, containing a sterically hindered cyclic N-hydroxy group, upon oxidation with lead dioxide in acetone, virtually quantitatively form stable nitroxyl bicyclic radicals of a new class, which are derivatives of both 2,2,6,6-tetramethyl-4-oxopiperidine-1-oxyl (TEMPON) and 3-imidazolines.