N-oxide Derivatives Research Articles

Photoinduced Copper-Catalyzed Cross-Coupling of Acylsilanes with Heteroarenes via Bimetallic Relay.

The transition metal-catalyzed direct coupling reactions involving electron-rich Fischer carbene species are largely underdeveloped and remain a big challenge. Here, a direct coupling reaction of azoles and azine N-oxides is reported with Fischer copper carbene species bearing an α-siloxy group i, which can be in situ generated from acylsilanes catalytically under photoirradiation and redox-neutral conditions. This coupling reaction between electron-rich α-siloxy Fischer Cu-carbene species with hard carbanion nucleophiles may undergo a bimetallic relay process, which is confirmed by the kinetic analysis and in situ NMR analysis. This reaction features mild conditions and remarkable heterocycle compatibility. Notably, this protocol tolerates a series of azole or azine N-oxide derivatives, including benzoxazole, benzothiazole, benzoimidazole, benzoisoxazole, oxazole, oxadiazole, triazolo[4,3-a]pyridine, purine, caffeine, pyridine N-oxide, quinoline N-oxide, pyrazine N-oxide, pyridazine N-oxide, etc. The synthetic value of this approach is demonstrated by the efficient synthesis of a histamine h4 receptor ligand and a marketed drug carbinoxamine.

Discovery of Potent Isoquinolinequinone N-Oxides to Overcome Cancer Multidrug Resistance.

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.

The photochemical isomerization in pyridazine-N-oxide derivatives

DFT calculations on the photoisomerization reactions of pyridazine N-oxide derivatives are presented. The irradiation of 3,6-diphenylpyridazine N-oxide allowed to obtain the first excited singlet state that underwent to a ring opening reaction induced to the oxygen migration to the adjacent carbon atom, with the formation of a diazo derivative. This intermediate can give a ring closure reaction to give a pyrazole derivative, or, with a higher transition energy, it can lose nitrogen allowing the formation of 2,5-diphenylfuran. The irradiation of 3-phenylpyridazine N-oxide allowed the formation only of 2-phenylfuran. In this case, calculations allowed to explain this behavior. The first excited singlet state gave a photoisomerization reaction with the formation of the corresponding diazo intermediate. This intermediate could not be converted into the corresponding pyrazole derivative because it was converted into a N-formyl pyrazole never reported in literature. The only possible reaction is the loss of nitrogen and the formation of 2-phenylfuran.

In vitro and In vivo Activity of a New N-Oxide Derivative for Acne Vulgaris Treatment.

Furoxan and benzofuroxan are compounds containing an N-oxide function, known for their diverse pharmacological properties, including antimicrobial and antiinflammatory effects. This study aimed to investigate these activities using an in-house library of N-oxide compounds. Twenty compounds were tested against both Gram-positive and Gram-negative bacteria, including Cutibacterium acnes (C. acnes), a microorganism implicated in the development of acne vulgaris. One compound, (E)-4-(3-((2-(3-hydroxybenzoyl)hydrazone)methyl)phenoxy)-3- (phenylsulfonyl)-1,2,5-oxadiazol-2-N-oxide (compound 15), exhibited selective antimicrobial activity against C. acnes, with a Minimum Inhibitory Concentration (MIC) value of 2 μg/mL. Indirect measurement of Nitric Oxide (NO) release showed that compound 15 and isosorbide dinitrate, when treated with L-cysteine, produced nitrite levels of 20.1% and 9.95%, respectively. Using a NO scavenger (PTIO) in combination with compound 15 in a culture of C. acnes resulted in reduced antimicrobial activity, indicating that NO release is part of its mechanism of action. Cytotoxicity assessments using murine macrophages showed cellular viability above 70% at concentrations up to 0.78 μg/mL. Measurements of Interleukin-1 beta (IL1-β) and Tumor Necrosis Factor-alpha (TNF-α) indicated that compound 15 did not reduce the levels of these pro-inflammatory cytokines. Sustained NO production by inducible Nitric Oxide Synthase (iNOS) in macrophages or neutrophils has been found to be involved in the inflammatory process in acne vulgaris and lead to toxicity in surrounding tissues. Nitrite levels in the supernatant of murine macrophages were found to be decreased at a concentration of 0.78 μg/mL of compound 15, indicating an anti-inflammatory effect. In vivo studies were conducted using Balb/c nude mice inoculated subcutaneously with C. acnes. Cream and gel formulations of compound 15 were applied to treat the animals, along with commercially available anti-acne drugs, for 14 days. Animals treated with a cream base containing 5% of compound 15 exhibited less acanthosis with mild inflammatory infiltration compared to other groups, highlighting its anti-inflammatory properties. Similar results were observed in the benzoyl peroxide group, demonstrating that compound 15 presented comparable anti-inflammatory activity to the FDA-approved drug. These promising results suggest that compound 15 has a dual mechanism of action, with selective antimicrobial activity against C. acnes and notable anti-inflammatory properties, making it a potential prototype for developing new treatments for acne vulgaris.

Synthesis and Crystallographic Characterization of Heteroleptic Ir(III) Complexes Containing the N-oxide Functional Group and Crystallographic Characterization of Ir(III) N-oxide Precursors

The N-oxide functional group has been exploited for synthetic strategies and drug design, and it has been utilized in imaging agents. Herein, we present rare examples of neutral heteroleptic cyclometallated Ir(III) compounds that contain an uncoordinated N-oxide functional group. These species, along with others described within, were verified by NMR, EA, HRMS, and single-crystal X-ray analysis. N-oxide-containing Ir(III) species were prepared selectively in high yields > 66% from chloro-bridged Ir(III) dimers with Acipimox, a picolinate-type ligand containing the N-oxide functional group. Non-N-oxide analogs were synthesized in a similar fashion (yields > 77%). Electrochemical comparison (cyclic voltammetry) indicates that the presence of an N-oxide functional group anodically shifts the reduction potential, suggesting that the N-oxide is acting as an electron-withdrawing group in these species. Crystallographic studies were pursued to examine the coordination behavior of these N-oxides compared to their non-oxidized congeners. The Ir(III) complexes with Acipimox indeed leave the N-oxide uncoordinated and exposed on the complexes. The uncoordinated N-oxide group is influential in directing the packing structures of these complexes directly through C-H···O and O···π interactions at the N-oxide. The crystallographic characterization of cationic Ir(III) compounds with uncoordinated nitrogen atoms is also presented. The C-H···N interactions between these complexes form a variety of dimers, finite chains, and continuous chains. Future work will focus on functionalizing the cationic Ir(III) species into their corresponding N-oxide derivatives and rigorously characterizing how the N-oxide functional group impacts the optical properties of transition metal compounds in both cationic and neutral complexes.

Synthetic Protocols and Applications of 1,2,5-Oxadiazoles: A Review

Abstract: The 1,2,5-oxadiazole framework has garnered a lot of interest among many nitrogen heterocycles because of its capacity to give off NO under physiological circumstances. Because of this, major efforts by chemical scientists have been made to create novel drug possibilities in medicinal, material, and agriculture science that include the NO-donor 1,2,5-oxadiazole N-oxide subunit coupled to a known drug or a possible pharmacophore by C-C/C-N links or by using a suitable spacer. In the last few years, 1,2,5-oxadiazole and its derivatives have been reported as good pharmacophores as carbonic anhydrase inhibitors, antibacterial, vasodilating agents, antimalarial, anticancer, etc. In the presented manuscript, we reviewed granted patents (last 10 years), different synthetic strategies (last 27 years) of 1,2,5- oxadiazoles and their N-oxide derivatives synthesis such as cycloaddition, dimerization, cyclodehydration, condensation, thermolysis, nitration, oxidation, ring-conversion, etc. These synthetic methods have also been analyzed for their merits and demerits. The manuscript also highlighted various applications of 1,2,5-oxadiazole and its derivatives. We hope that researchers across the scientific streams will benefit from the presented review articles for designing their work related to 1,2,5-oxadiazoles.

Експериментальне дослідження гепатопротекторної дії комплексу n-оксид-2,6-диметил піридину з бурштиновою кислотою (Потейтіну) на моделі токсичного гепатиту, спричиненого тетрахлорметаном

Plant growth regulators (PGR), in particular, methyl derivatives of pyridine N-oxide, reduce the acute toxicity of pesticides, reduce the hepatotoxic effects of chlorpyrifos and ease the course of intoxication under long-term exposure. The role of the body’s defence systems under the combined effects of PGR and pesticides has not yet been sufficiently elucidated. The study of the protective effect of PGR Poteitin under the conditions of toxic damage to the liver by carbon tetrachloride (CCl4) will allow finding out the mechanisms of its combined action. The results of the research will be used to develop preventive measures for pesticide poisoning. Aim. Investigate the hepatoprotective properties of the 2.6-dimethylpyridine N-oxide complex with succinic acid (Poteitin) on the model of acute hepatitis caused by carbon tetrachloride. Materials and Methods. Acute hepatitis was modelled on male Wistar Han rats with subcutaneous injection of CCl4 (pure substance) in petroleum jelly oil (0.8 ml/100 g of body weight) for 2 days. Poteitin was administered at the doses of 23 and 0.23 mg/kg, reference substance Silybor 35 – at the dose of 5 mg/kg. Intact rats received petroleum jelly oil in the same volumes. Poteitin and Silybor were administered in a treatment-prophylactically regimen, orally 1 hour pre- and 2 hours post-CCl4. The activity of enzymes of cytolysis and cholestasis, indicators reflecting liver function, the content of lipid peroxidation (LP) products and antioxidant activity were determined in blood serum. Histological studies of liver tissue were carried out. The index of effectiveness of the protective effect of Poteitin was calculated The results were statistically processed using the one-way ANOVA followed by Fisher's LSD post-hoc test. Results and Discussion. CCl4 caused acute liver damage: increased activity of markers of cytolysis and cholestasis, decrease in a number of functional tests, activity of catalase, LP products accumulation, fatty and balloon dystrophy of hepatocytes, lympho-leukocyte infiltration. Poteitin on the background of CCl4 contributed to the normalization of the activity of markers of cytolysis and cholestasis, the restoration of functional indicators, reduced the content of LP products, increased the activity of catalase, and reduced liver damage. The protective effect of Poteitin was not inferior to Silybor. Conclusions. 1. Under the conditions of acute hepatitis, carbon tetrachloride causes moderate liver damage. 2. Poteitin at the doses of 23 and 0.23 mg/kg has a pronounced hepatoprotective effect: it normalizes the activity of enzymes of cytolysis and cholestasis, functional indicators – the level of glucose, cholesterol, total protein and bilirubin, urea; reduces the intensity of LP and activation of the antioxidant system. 3. The protective effect of Poteitin at both tested doses as cytolysis and cholestasis indicators, functional tests and morphostructural changes in the liver is comparable to the reference drug Silybor. The protective effect of Poteitin, determined by the intensity of LP, is greater than that of Silybor. Keywords: acute hepatitis, carbon tetrachloride, hepatoprotective effect, 2.6-dimethylpyridine N-oxide complex with succinic acid.

Structural, spectroscopic properties ant prospective application of a new nitropyridine amino N-oxide derivative: 2-[(4-nitropyridine-3-yl)amino]ethan-1-ol N-oxide

A new nitropyridine amino N-oxide derivative 2-[(4-nitropyridine-3-yl)amino]ethan-1-ol N-oxide was synthesized and its structural and optical properties were described. Its structure obtained from the X-ray diffraction (XRD) studies was related to the Infrared spectroscopy (IR), Raman spectroscopy (RS), electron Ultraviolet–Visible spectroscopy (UV–VIS) and emission spectra measurements. The experimental results were analyzed in terms of theoretical data obtained from quantum chemical Density Functional Theory (DFT) and Natural Bond Orbital (NBO) calculations. The 6-311G(2d,2p) basis set with the B3LYP functional was used to discuss its optimized structure and vibrational properties. Femtosecond excitation was used to recognize the depopulation mechanism of the electron excited states in the studied compound. It was found that the intermolecular interactions strongly influence the physicochemical properties and application of the new nitropyridine amino N-oxide derivative.

Стан прооксидантної та антиоксидантної систем організму щурів за умов однократної дії деяких метильних похідних N-оксид піридину – Івіну і Потейтіну

АBSTRACT. Previously, it was shown that pyridine N-oxide based plant growth regulators (PGR) Ivin and Poteitin when combined with pesticides reduce the acute and subchronic toxicity of pesticides for mammals, have a hepatoprotective effect, contribute to the reduction of mutagenic activity, in particular, of Cyclophosphane and Dioxidin cytostatics (Vasetska O.P., 2017, Vasetska O.P. et al., 2020, 2021). It is possible that a wide range of their biological effects may be associated with the activation of the body’s protective systems, in particular the antioxidant system. The effect of these PGRs on the state of the pro-oxidant and antioxidant systems is not sufficiently clarified. Therefore, an important issue for preventive toxicology is the study of the nature of the effect of PGR on the state of the body’s pro-oxidant and antioxidant systems, which will contribute to the development of preventive measures to preclude acute and chronic intoxications with pesticides. Aim. To find out the state of the body’s pro-oxidant and antioxidant systems under a single oral exposure to some plant growth regulators –pyridine N-oxide methyl derivatives. Materials and Methods. For the aim of this research we used PGR 2.6-dimethyl- pyridine N-oxide (Ivin) and a complex of 2.6- dimethylpyridine-N-oxide with succinic acid (Poteitin). PGR in the form of an aqueous solution was administered to male Wistar Han rats orally with a probe: Ivin at doses of 650 mg/kg (1/2 LD50) and 13 mg/kg (1/100 LD50), Poteitin – at doses of 1150 mg/kg (1/2 LD50) and 23 mg/kg (1/100 LD50). The influence of Ivin and Poteitin on the lipid peroxidation (LPO) and the antioxidant system under a single oral exposure to the body of male rats was determined on days 1, 3, and 7. LPO in liver tissues was determined by the content of malondialdehyde (MDA), diene conjugates (DC), ketodienes (KD), conjugated trienes (CT) and Schiff bases (SB). MDA level was determined by the reaction with 2-thiobarbituric acid, DC, KD, CT, and SB in liver tissues – by the extraction-spectrophotometric method. The antioxidant status of the body was assessed by the activity of the catalase enzymes (CAT), glutathione peroxidase (GP), glutathione reductase (GR), the content of reduced glutathione (GSH) and total antioxidant activity (AOA). The results of the research were estimated by standard methods of variational statistics according to Student’s t-test criterion. Results. It was established that Ivin in the researched doses in the heptane fraction reduces the LPO intensity (containing MDA, DC, SB) in the liver tissues of rats, in the isopropanol fraction – DC; increases the activity of catalase and total AOA in blood serum. Poteitin in the tested doses in the heptane fraction reduces the formation of lipid products (containing MDA, DC, KD and CT) in the liver tissues of rats, in the isopropanol fraction – DC; increases the activity of catalase and the content of GSH, total AOA. Both substances do not disrupt the glutathione system. Compared to Ivin, Poteitin has a more pronounced effect on the intensity of LPO and the activity of the antioxidant system. Conclusions. 1. Plant growth regulators Ivin and Poteitin, at a single exposure to the body of male rats in doses corresponding to 1/2 and 1/100 LD50, reduce pro-oxidant activity, do not disrupt the glutathione system, increase the activity of the antioxidant system. 2. Increase in the activity of the antioxidant system and inhibition of the intensity of lipid peroxidation processes both under the influence of Ivin and Poteitin are aimed at adapting the body to the chemical factor. 3. Activation of the antioxidant system together with a decrease in the intensity of LPO can be one of the mechanisms of protection of the body from the toxic effects of pesticides when they are simultaneously introduced into the body with plant growth regulators based on methyl derivatives of pyridine N-oxide. Key words: plant growth regulators, Ivin, Poteitin, prooxidant and antioxidant systems.

General and selective homogeneous Ru-catalyzed transfer hydrogenation, deuteration, and methylation of functional compounds using methanol

Catalytic valorization of methanol in organic synthesis and energy technologies is interesting and important for both fundamental research and industrial applications. In particular, its utilization as hydrogen, deuterium and methyl sources for selective reduction and deuteration reactions as well as to access N-methylated products is highly desirable and can be considered as a potential methodology for the amplification of transfer hydrogenation and C1 chemistry. Here, we report homogeneous Ru-MACHO complex catalyzed transfer hydrogenation of different functionalized compounds such as ketones, aldehydes, alkynes, alkenes, imines, azobenzenes, and nitro compounds as well as deoxygenation of N-oxide derivatives employing methanol as an affordable hydrogen donor and solvent. This Ru-based strategy has been proven to be very convenient for the deuteration process to synthesize advanced deuterium-labelled compounds, including the gram-scale synthesis of deuterated pharmaceuticals such as d-Cloperastine, d-Buclizine, d-Diphendyarmine, d-Modafinil, and d-Adrafinil using CD3OD. In addition, the application of methanol as a C1 source for the preparation of N-methylated products is showcased. Finally, kinetic and mechanistic investigations for this Ru-catalyzed transfer hydrogenation and deuteration protocols have been performed.

Orally bioavailable styryl derivative of rohitukine-N-oxide inhibits CDK9/T1 and the growth of pancreatic cancer cells

The chromone alkaloid is one of the classical pharmacophores for cyclin-dependent kinases (CDKs) and represents the first CDK inhibitor to reach clinical trials. Rohitukine (1), a chromone alkaloid isolated from Dysoxylum binectariferum inspired the discovery of several clinical candidates. The N-oxide derivative of rohitukine occurs naturally, with no reports on its biological activity. Herein, we report isolation, biological evaluation, and synthetic modification of rohitukine N-oxide for CDK9/T1 inhibition and antiproliferative activity in cancer cells. Rohitukine N-oxide (2) inhibits CDK9/T1 (IC50 7.6 μM) and shows antiproliferative activity in the colon and pancreatic cancer cells. The chloro-substituted styryl derivatives, 2b, and 2l, inhibit CDK9/T1 with IC50 values of 0.17 and 0.15 μM, respectively. These derivatives display cellular antiproliferative activity in HCT 116 (colon) and MIA PaCa-2 (pancreatic) cancer cells with GI50 values of 2.5–9.7 μM with excellent selectivity over HEK293 (embryonic kidney) cells. Both analogs induce cell death in MIA PaCa-2 cells via inducing intracellular ROS production, reducing mitochondrial membrane potential, and inducing apoptosis. These analogs are metabolically stable in liver microsomes and have a decent oral pharmacokinetics in BALB/c mice. The molecular modeling studies indicated their strong binding at the ATP-binding site of CDK7/H and CDK9/T1.

Tetrahydroquinazoline N-oxide derivatives inhibit reproduction of tick-borne and mosquito-borne flaviviruses.

Tick-borne encephalitis virus (TBEV), yellow fever virus (YFV), and West Nile virus (WNV) are flaviviruses causing emerging arthropod-borne infections of a great public health concern. Clinically approved drugs are not available to complement or replace the existing vaccines, which do not provide sufficient coverage. Thus, the discovery and characterization of new antiflaviviral chemotypes would advance studies in this field. In this study, a series of tetrahydroquinazoline N-oxides was synthesized, and the antiviral activity of the compounds was assessed against TBEV, YFV, and WNV using the plaque reduction assay along with the cytotoxicity to the corresponding cell lines (porcine embryo kidney and Vero). Most of the studied compounds were active against TBEV (EC50 2 to 33 μM) and WNV (EC50 0.15 to 34 μM) and a few also demonstrated inhibitory activity against YFV (EC50 0.18 to 41 μM). To investigate the potential mechanism of action of the synthesized compounds, time-of-addition (TOA) experiments and virus yield reduction assays were performed for TBEV. The TOA studies suggested that the antiviral activity of the compounds should affect the early stages of the viral replication cycle after cell entry. Compounds with tetrahydroquinazoline N-oxide scaffold show a broad spectrum of activity against flaviviruses and represent a promising chemotype for antiviral drug discovery.

Insensitive High-Energy Density Materials Based on Azazole-Rich Rings: 1,2,4-Triazole N-Oxide Derivatives Containing Isomerized Nitro and Amino Groups.

It is an arduous and meaningful challenge to design and develop new energetic materials with lower sensitivity and higher energy. How to skillfully combine the characteristics of low sensitivity and high energy is the key problem in designing new insensitive high-energy materials. Taking a triazole ring as a framework, a strategy of N-oxide derivatives containing isomerized nitro and amino groups was proposed to answer this question. Based on this strategy, some 1,2,4-triazole N-oxide derivatives (NATNOs) were designed and explored. The electronic structure calculation showed that the stable existence of these triazole derivatives was due to the intramolecular hydrogen bond and other interactions. The impact sensitivity and the dissociation enthalpy of trigger bonds directly indicated that some compounds could exist stably. The crystal densities of all NATNOs were larger than 1.80 g/cm3, which met the requirement of high-energetic materials for crystal density. Some NATNOs (9748 m/s for NATNO, 9841 m/s for NATNO-1, 9818 m/s for NATNO-2, 9906 m/s for NATNO-3, and 9592 m/s for NATNO-4) were potential high detonation velocity energy materials. These study results not only indicate that the NATNOs have relatively stable properties and excellent detonation properties but also prove that the strategy of nitro amino position isomerization coupled with N-oxide is an effective means to develop new energetic materials.

2,6-Disubstituted Piperidine Alkaloids with Neuroprotective Activity from Hippobroma longiflora.

Three new alkaloids, hipporidine A (1: ), hipporidine B (2: ), and (-)-lobeline N-oxide (3: ), were discovered from the whole plant of Hippobroma longiflora together with five known compounds (4: -8: ). Their 2,6-disubstituted piperidine structures were established based on the HRESIMS, NMR (COSY, HMBC, HSQC, NOESY), and UV spectroscopic data. Hipporidines A (1: ) and B (2: ) possess a rare 1,3-oxazinane moiety. Compound 3: is the N-oxide derivative of (-)-lobeline (6: ). Moreover, the absolute configuration of norlobeline (5: ) was established by single-crystal X-ray diffraction analysis. Three major secondary metabolites (6: -8: ) were evaluated for their neuroprotective effect against paclitaxel-induced neurotoxicity. Consequently, pretreatment with compound 8: at a concentration of 1.0 µM displayed significant attenuation on paclitaxel-damaged neurite outgrowth of dorsal root ganglion neurons without interfering with the cytotoxicity of paclitaxel on cervical cancer SiHa cells.

Novel 7-Chloro-(4-thioalkylquinoline) Derivatives: Synthesis and Antiproliferative Activity through Inducing Apoptosis and DNA/RNA Damage.

A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5–40 and sulfinyl 41–62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63–82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53−/− (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates.

Ultrafast excited state dynamics of pyridine N-oxide derivative in solution; femtosecond fluorescence up-conversion and theoretical calculations

In this study we have investigated 2-ethylamino-4-nitro-6-methyl pyridine N-oxide (2E6M) molecule that belongs to important group of Proton Coupled Electron Transfer (PCET) compounds where both the charge transfer (CT) and proton transfer processes in excited states may proceed. In this case, this is possible due to the donors and acceptors of electrons and protons in this system, as well as due to the presence of intramolecular {N-H… O [2,566(3) Å}, hydrogen bond.Using stationary and time-resolved spectroscopy, as well as quantum chemical calculations on the DFT and TD DFT B3LYP/6-31G (d,p) level of theory, a partial CT nature of the S0 → S1 transition in both tautomeric forms (N and T) has been revealed. Additionally, the excited state intramolecular proton transfer (ESIPT) process shown to be more favorable in apolar and weakly polar solvents than in strongly polar acetonitrile (EN(S1) > ET(S1). The displacement of charge from the amine group and the ring to the nitro group has been observed on the changing shapes of the HOMO and LUMO orbitals involved in this transition what further quantitatively allowed to realize the increase in the dipole moment of both forms in the electronic excited state. The calculations show that in two solvents with radically different polarity (heptane, acetonitrile), dipole moments of both forms are very similar [in acetonitrile uN(S1) and uT(S1) are 11.0 D and 11.5 D, respectively]. Hence, in polar media both forms can be stabilized in a comparable manner. This made it difficult for us to assign a single fluorescent band in acetonitrile to one of the tautomeric forms. However, it seems that due to application of time-resolved spectroscopy, this problem has been clarified. The TCSPC decay curve in acetonitrile with an ultrafast lifetime assigned to the (N) form, along with the femtosecond up-conversion signals that demonstrated only an ultrafast decay without any rise-time of a new excited (T) species, allowed us to conclude that in 2E6M in strongly polar solvent the ESIPT does not occur.The unique fluorescence band origins from the (N) form. In protic solvents, the significant kinetic isotopic effects have provided us with conclusive evidence for the presence of the solvent-assisted ESIPT process. Furthermore, it was noticed that the fluorescence lifetime in D2O (100–120 fs) estimated from the up-conversion signals is about 40 times shorter relative to methanol. This may suggest that the sine qua non for the ESIPT process in 2E6M in protic solvents is the formation of a complex with a solvent molecule in the hydrogen bridge between the proton donor and proton acceptor, respectively.

Exploring Intra- and Intermolecular Interactions in Selected N-Oxides-The Role of Hydrogen Bonds.

Intra- and intermolecular interactions have been explored in selected N-oxide derivatives: 2-(N,N-dimethylamino-N-oxymethyl)-4,6-dimethylphenyl (1) and 5,5’-dibromo-3-diethylaminomethyl-2,2’-biphenol N-oxide (2). Both compounds possess intramolecular hydrogen bonding, which is classified as moderate in 1 and strong in 2, and resonance-assisted in both cases. Density Functional Theory (DFT) in its classical formulation as well as Time-Dependent extension (TD-DFT) were employed to study proton transfer phenomena. The simulations were performed in the gas phase and with implicit and explicit solvation models. The obtained structures of the studied N-oxides were compared with experimental data available. The proton reaction path was investigated using scan with an optimization method, and water molecule reorientation in the monohydrate of 1 was found upon the proton scan progress. It was found that spontaneous proton transfer phenomenon cannot occur in the electronic ground state of the compound 1. An opposite situation was noticed for the compound 2. The changes of nucleophilicity and electrophilicity upon the bridged proton migration were analyzed on the basis of Fukui functions in the case of 1. The interaction energy decomposition of dimers and microsolvation models was investigated using Symmetry-Adapted Perturbation Theory (SAPT). The simulations were performed in both phases to introduce polar environment influence on the interaction energies. The SAPT study showed rather minor role of induction in the formation of homodimers. However, it is worth noticing that the same induction term is responsible for the preference of water molecules’ interaction with N-oxide hydrogen bond acceptor atoms in the microsolvation study. The Natural Bond Orbital (NBO) analysis was performed for the complexes with water to investigate the charge flow upon the polar environment introduction. Finally, the TD-DFT was applied for isolated molecules as well as for microsolvation models showing that the presence of solvent affects excited states, especially when the N-oxide acceptor atom is microsolvated.

Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity.

Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 μM against L. infantum amastigote forms and CC50 value superior to 500 μM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 μM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.

Molecular Electrostatic Potential and Noncovalent Interactions in Derivatives of Group 8 Elements.

This communication reports experimental and theoretical evidences of σ‐hole interactions in adducts between nitrogen or oxygen nucleophiles and tetroxides of osmium or other group 8 elements. Cocrystals between pyridine or pyridine N‐oxide derivatives and osmium tetroxide are characterized through various techniques and rationalized as σ‐hole interactions using DFT calculations and several other computational tools. We propose the term “osme bond” (OmB, Om=Fe, Ru, Os, (Hs)) for naming the noncovalent interactions wherein group 8 elements have the role of the electrophile. The word osme is the transcription of ὀσμή, the ancient Greek word for smell that was used to name the heaviest group 8 element in relation to the smoky odor of its tetroxide.

Synthesis and analytical characterization of monomeric N-oxidized derivatives of \u03b1-tocopheramine

α-Tocopheramine has shown great promises as a stabilizer for synthetic and natural polymers, but is also investigated in various biomedical scenarios. Many studies have been hampered by the fact that the oxidation products of α-tocopheramine have not yet been properly identified and their analytical data are still lacking. In the present study, we synthesized and fully analytically characterized all N-oxidation products that can form upon oxidation of α-tocopheramine in aqueous media, including the hydroxylamine, nitroso, and nitro derivative, in this way providing standards for the identification of the so far elusive byproducts. Synthesis and stability of the derivatives are discussed.Graphic abstract