Search Results (29)

This study aimed to determine the pharmacokinetic profile of the active dipyrone metabolites, 4-methylaminoantipyrine and 4-aminoantipyrine, following intravenous administration in dogs. Eleven mixed-breed dogs received a 25 mg·kg⁻¹ dipyrone dose and blood samples were collected at 0, 5, 15, 30 and 45 min, as well as at 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 h. Plasma concentrations of both metabolites were analyzed by ultra-performance liquid chromatography coupled to mass spectrometry. The PKSolver 2.0 and GraphPad Prisma 10 software programs were used for pharmacokinetic and statistical analyses, applying a Principal Component Analysis for MAA and descriptive statistics for both metabolites. Two groups were noteworthy concerning MAA: slow metabolizers (SM) and normal/rapid metabolizers (NM). Significant differences were observed between half-life (T_½) and MRT_{0_inf obs} values between the MAA groups. The T_½ and MRT_{0_info obs} were 44.44 ± 11.74 and 32.62 ± 16.53 h for the SM group and 11.25 ± 5.37 and 7.44 ± 4.25 h for the NM group, respectively. The C_max of AA was 2.80 ± 1.43 µg mL⁻¹. Metabolites were detectable for 48 h in all animals for MAA and seven for AA. These findings suggest that metamizole reaches analgesia plasma concentrations associated with cyclooxygenase inhibition with few adverse effects in dogs. However, additional pharmacogenetic and pharmacotherapeutic monitoring studies are required. Full article

Metamizole (dipyrone) is a non-opioid analgesic widely used in human and veterinary medicine, despite ongoing concerns about its safety due to risks such as agranulocytosis and potential hepatotoxicity. This study investigates the cytotoxic (MTT assay) and pro-apoptotic effects of metamizole and its primary metabolites, 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA), on the LX-2 liver cell line. These metabolites are implicated in both the therapeutic and adverse effects of the drug. The objective is to elucidate the mechanisms of potential hepatotoxicity, with a focus on cell viability and apoptosis. Metamizole was tested at five concentrations (100, 200, 400, 600, and 1000 µg/mL), while its metabolites were tested at two concentrations (100 and 1000 µg/mL). The results show a dose-dependent decrease in cell viability, with significant reductions at higher concentrations. The greatest cytotoxic effects were observed with 4-AA and 4-MAA, which induced marked apoptosis at 1000 µg/mL. This study concludes that metamizole and its metabolites can cause liver cell damage, underscoring the importance of caution in its clinical use and the need for further research to ensure its safety. Full article

Our objective was to assess the pharmacokinetic characteristics of metamizole when administered together with tramadol in a single intravenous dose to donkeys. Ten male animals received 10 mg∙kg⁻¹ of dipyrone associated with 2 mg∙kg⁻¹ of tramadol (T₂M₁₀) and 25 mg∙kg⁻¹ of dipyrone with 2 mg∙kg⁻¹ of tramadol (T₂M₂₅). Venous blood samples were taken from groups to determine the pharmacokinetics after drug administration, using initial brief intervals that were followed by extended periods until 48 h. Restlessness and ataxia were observed in two animals in the T₂M₂₅ group. Analysis revealed prolonged detectability of tramadol, 4-methylamine antipyrine, 4-aminoantipyrine (up to 24 h), and O-desmethyltramadol (up to 12 h) after administration. Although metamizole and its metabolites showed no significant pharmacokinetic changes, tramadol and O-desmethyltramadol exhibited altered profiles, likely because of competition for the active sites of CYP450 enzymes. Importantly, the co-administration of metamizole increased the bioavailability of tramadol and O-desmethyltramadol in a dose-dependent manner, highlighting their potential interactions and emphasizing the need for further dose optimization in donkey analgesic therapies. In conclusion, metamizole co-administered with tramadol interferes with metabolism and this interference can change the frequency of drug administration and its analgesic efficacy. Full article

The functionalized graphene oxide (GO)-based composites as fillers added into organic coatings are desired for realizing the longstanding corrosion protection of carbon steel. Here, the pH-responsive two-dimensional/three-dimensional (2D/3D) GO-based composite (ZIF–90–AAP/GO) was developed by environmentally friendly corrosion inhibitor 4-aminoantipyrine (AAP) anchored on the in situ growth of zeolite imidazolate framework–90 (ZIF–90) on the GO surface (ZIF–90/GO) through the Schiff base reaction. The active filler (ZIF–90–AAP/GO) was incorporated into an epoxy coating (EP) to obtain a high-performance self-healing coating on the surface of carbon steel. ZIF–90–AAP can greatly improve dispersion and compatibility of GO in EP. The low-frequency impedance modulus of ZIF–90–AAP/GO–EP can still reach up to 1.35 × 10¹⁰ Ω⋅cm² after 40 days, which is about three orders of magnitude higher than that of the EP containing GO (GO–EP) relying on its passive and active corrosion protection. Meanwhile, ZIF–90–AAP/GO–EP exhibits excellent self-healing performance. The self-healing rate of ZIF–90–AAP/GO changes from negative to positive after 24 h, which results from the effective corrosion inhibition activity of ZIF–90–AAP for carbon steel based on the pH-triggered controlled release of AAP. The developed pH-responsive 2D/3D GO-based composite coating is very attractive for the corrosion protection of carbon steel. Full article

The synthesis, characterization, and anticancer properties of three imine-type compounds 1–3 and an unexpected oxazine derivative 4 are presented. The reaction of p-dimethylaminobenzaldehyde or m-nitrobenzaldehyde with hydroxylamine hydrochloride afforded the corresponding oximes 1–2 in good yields. Additionally, the treatment of benzil with 4-aminoantipyrine or o-aminophenol was investigated. Routinely, the Schiff base (4E)-4-(2-oxo-1,2-diphenylethylideneamino)-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one 3 was obtained in the case of 4-aminoantipyrine. Unexpectedly, the reaction of benzil with o-aminophenol proceeded with cyclization to produce the 2,3-diphenyl-2H-benzo[b][1,4]oxazin-2-ol 4. The structures of compounds 3 and 4 were unambiguously determined by single crystal X-ray diffraction. Hirshfeld analysis of molecular packing revealed the importance of the O…H (11.1%), N…H (3.4%), C…H (29.4%), and C…C (1.6) interactions in the crystal stability of 3. In the case of 4, the O…H (8.8%), N…H (5.7%), and C…H (30.3%) interactions are the most important. DFT calculations predicted that both compounds have a polar nature, and 3 (3.4489 Debye) has higher polarity than 4 (2.1554 Debye). Different reactivity descriptors were calculated for both systems based on the HOMO and LUMO energies. The NMR chemical shifts were calculated and were found well correlated with the experimental data. HepG2 growth was suppressed by the four compounds more than MCF-7. The IC₅₀ values of 1 against HepG2 and MCF-7 cell lines were the lowest, and it is considered the most promising candidate as an anticancer agent. Full article

Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB₁ and CB₂ appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7–11) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50–80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by N-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB₁- or CB₂-transfected cells, compounds demonstrated an inverse agonist profile on CB₂ receptors and the further characterization of compound LASSBio-2265 (11) revealed moderate binding affinity to CB₂ receptor (K_i = 16 µM) with an EC₅₀ = 0.36 µM (E_max = 63%). LASSBio-2265 (11) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases. Full article

Schiff bases have been important compounds ever since their discovery and are both found in nature and synthesized in the laboratory. They participate in a variety of synthetic processes and possess desirable biological activity, including antibacterial, anti-inflammatory, antioxidant, and anticancer activity, among others. In this study, eight Schiff bases derived from the reaction of 4-aminoantipyrine with various cinnamaldehydes have been synthesized and characterized. All derivatives were tested in vitro on several human carcinoma cell lines to determine their antitumor activity and against different bacteria strains of clinical and food industry importance to evaluate their antibacterial activity. Several of the Schiff bases evaluated inhibited tumor cell growth in a dose-dependent manner. The compound that exhibited the most activity against all cell lines had IC₅₀ values of less than 18 μM. On the other hand, during the evaluation of the antibacterial activity, only two Schiff base derivatives showed interesting antibacterial effects, with MIC values under 250 μM. These two Schiff base derivatives mainly exhibited a bacteriostatic effect against most of the studied bacterial strains. It is interesting to note that the same Schiff base presents the best activity in both biological evaluations. Full article

A mononuclear Co(II) complex of a Schiff base ligand derived from 5-Bromo-vanillin and 4-aminoantipyrine, that has a compressed tetragonal bipyramidal geometry and exhibiting field-induced slow magnetic relaxation, has been synthesized and characterized by single crystal X-ray diffraction, elemental analysis and molecular spectroscopy. In the crystal packing, a hydrogen-bonded dimer structural topology has been observed with two distinct metal centers having slightly different bond parameters. The complex has been further investigated for its magnetic nature on a SQUID magnetometer. The DC magnetic data confirm that the complex behaves as a typical S = 3/2 spin system with a sizable axial zero-field splitting parameter D/hc = 38 cm⁻¹. The AC susceptibility data reveal that the relaxation time for the single-mode relaxation process is τ = 0.16(1) ms at T = 2.0 K and B_DC = 0.12 T. Full article

Levosimendan is used in severe chronic cardiac insufficiency, also within the peri-operative setting. Real-life pharmacokinetic data in surgical patients is lacking, making therapeutic drug monitoring (TDM) of levosimendan, its pharmacologically active metabolite OR-1896, and its intermediate OR-1855 important. A simultaneous highly sensitive quantification of levosimendan and its metabolites in small-volume samples has not yet been described. Here, levosimendan (LLOQ 0.450 nM), OR-1896, and OR-1855 (LLOQ both 1.0 nM) were successfully quantified by LC-ESI-MS/MS after liquid-liquid extraction in 300 µL of blood. A short C8 column under reversed-phase conditions enabled simultaneous and fast quantification of levosimendan in the negative and the metabolites in the positive ionization mode in a single run within 2 min. Interestingly and unexpectedly, constitutional isomers of levosimendan metabolites with identical mass transitions and similar retention times were observed in surgical patients’ samples, which we identified as the metamizole metabolites 4-aminoantipyrine and 4-acetamidoantipyrine. A longer C8 column and a modified mobile phase enabled selective quantification of all analytes in a single run within 7 min. We developed, validated, and applied highly sensitive LC-ESI-MS/MS methods for simultaneous quantification of levosimendan and its metabolites, enabling efficient TDM of cardiac surgery patients even with additional metamizole administration. Full article

A simple and reliable dispersive liquid-liquid microextraction (DLLME) coupled with smartphone-based digital images using crude peroxidase extracts from cassia bark (Senna siamea Lam.) was proposed to determine carbaryl residues in Andrographis paniculata herbal medicines. The method was based on the reaction of 1-naphthol (hydrolysis of carbaryl) with 4-aminoantipyrine (4-AP) in the presence of hydrogen peroxide, using peroxidase enzyme simple extracts from cassia bark as biocatalysts under pH 6.0. The red product, after preconcentration by DLLME using dichloromethane as extraction solvent, was measured for blue intensity by daily life smartphone-based digital image analysis. Under optimized conditions, good linearity of the calibration graph was found at 0.10–0.50 mg·L⁻¹ (r² = 0.9932). Limits of detection (LOD) (3SD/slope) and quantification (LOQ) (10SD/slope) were 0.03 and 0.09 mg·L⁻¹, respectively, with a precision of less than 5%. Accuracy of the proposed method as percentage recovery gave satisfactory results. The proposed method was successfully applied to analyze carbaryl in Andrographis paniculata herbal medicines. Results agreed well with values obtained from the HPLC-UV method at 95% confidence level. This was simple, convenient, reliable, cost-effective and traceable as an alternative method for the determination of carbaryl. Full article

Considering the astounding biomedicine properties of pharmaceutically active drug, 4-aminophenazone, also known as 4-aminoantipyrine, the work reported in this manuscript details the formation of novel cocrystals of rearranged 4-aminophenazone and 4-nitro-N-(4-nitrobenzoyl) benzamide in 1:1 stoichiometry under employed conditions for thiourea synthesis by exploiting the use of its active amino component. However, detailed analysis via various characterization techniques such as FT-IR, nuclear magnetic resonance spectroscopy and single crystal XRD, for this unforeseen, but useful cocrystalline synthetic adduct (4 and 5) prompted us to delve into its mechanistic pathway under provided reaction conditions. The coformer 4-nitro-N-(4-nitrobenzoyl) benzamide originates via nucleophilic addition reaction following tetrahedral mechanism between para-nitro substituted benzoyl amide and its acid halide (1). While the enamine nucleophilic addition reaction by 4-aminophenazone on 4-nitrosubstituted aroyl isothiocyanates under reflux temperature suggests the emergence of rearranged counterpart of cocrystal named N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide. Crystallographic studies reveal triclinic system P-1 space group for cocrystal (4 and 5) and depicts two different crystallographically independent molecules with prominent C–H···O and N–H···O hydrogen bonding effective for structure stabilization. Hirshfeld surface analysis also displays hydrogen bonding and van der Waals interactions as dominant interactions in crystal packing. Further insight into the cocrystal synthetic methodologies supported the occurrence of solution-based evaporation/cocrystallization methodology in our case during purification step, promoting the synthesis of this first-ever reported novel cocrystal of 4-aminophenazone with promising future application in medicinal industry. Full article

Metamizole is an analgesic, whose pharmacological and toxicological properties are attributed to N-methyl-aminoantipyrine (MAA), its major metabolite. In the presence of heme iron, MAA forms reactive metabolites, which are toxic for granulocyte precursors. Since decreased cellular ATP is characteristic for MAA-associated toxicity, we studied the effect of MAA with and without hemin on energy metabolism of HL60 cells, a granulocyte precursor cell line. The combination MAA/hemin depleted the cellular ATP stronger than hemin alone, whereas MAA alone was not toxic. This decrease in cellular ATP was observed before plasma membrane integrity impairment. MAA/hemin and hemin did not affect the proton leak but increased the maximal oxygen consumption by HL60 cells. This effect was reversed by addition of the radical scavenger N-acetylcysteine. The mitochondrial copy number was not affected by MAA/hemin or hemin. Hemin increased mitochondrial superoxide generation, which was not accentuated by MAA. MAA decreased cellular ROS accumulation in the presence of hemin. In cells cultured in galactose (favoring mitochondrial ATP generation), MAA/hemin had less effect on the cellular ATP and plasma membrane integrity than in glucose. MAA/hemin impaired glycolysis more than hemin or MAA alone, and N-acetylcysteine blunted this effect of MAA/hemin. MAA/hemin decreased protein expression of pyruvate kinase more than hemin or MAA alone. In conclusion, cellular ATP depletion appears to be an important mechanism of MAA/hemin toxicity on HL60 cells. MAA itself is not toxic on HL60 cells up to 100 µM but boosts the inhibitory effect of hemin on glycolysis through the formation of reactive metabolites. Full article

Our main interest is the characterization of compounds to support the development of alternatives to currently marketed drugs that are losing effectiveness due to the development of resistance. Schiff bases are promising biologically interesting compounds having a wide range of pharmaceutical properties, including anti-inflammatory, antipyretic, and antimicrobial activities, among others. In this work, we have synthesized 12 Schiff base derivatives of 4-aminoantipyrine. In vitro antimicrobial, antioxidant, and cytotoxicity properties are analyzed, as well as in silico predictive adsorption, distribution, metabolism, and excretion (ADME) and bioactivity scores. Results identify two potential Schiff bases: one effective against E. faecalis and the other with antioxidant activity. Both have reasonable ADME scores and provides a scaffold for developing more effective compounds in the future. Initial studies are usually limited to laboratory in vitro approaches, and following these initial studies, much research is needed before a drug can reach the clinic. Nevertheless, these laboratory approaches are mandatory and constitute a first filter to discriminate among potential drug candidates and chemical compounds that should be discarded. Full article

The goal of this study was to determine the optimal chain length needed for tethering functional groups on bio-wastes. The purpose of modifying the surface of bio-waste is to improve their affinity for phenols. To this end, four different aminated green tea leaves, with the amine group located at the end of 6, 8, 10, and 12 carbons were synthesized. Green approaches to functionalization lead to fewer reactive sites. Optimizing spacer length is one way to ameliorate this. The aminated tea leaves were prepared by a tosylation reaction followed by displacement with a diamine used in excess. The tea leaves with the amine at the end of six carbons proved to have the best ability to remove 2-chlorophenol (2-CP) from its aqueous solution. It was at least 3–4 times better than native spent tea leaves. The mechanism by which the phenol was removed proved to be primarily an acid–base reaction followed by H-bonding and dipole–dipole interactions. Because of the acid–base interactions, the relatively low-boiling 2-CP did not volatilize off the aminated tea leaves enabling recycling. On the other hand, with activated charcoal, the adsorbed 2-CP volatilized almost completely under ambient conditions. Full article

Diazocoupling reaction of curcumin with different diazonium salts of p-toluidine, 2-aminopyridine, and 4-aminoantipyrine in pyridine yielded the arylhydrazones 2a–c. Arylhydrazone of p-toluidine reacted with urea, thiourea, and guanidine nitrate to produce 5,6-dihydropyrimidines. Further reaction of 2a with 2,3-diaminopyrdine in sodium ethoxide solution yielded 1H-pyrido[2,3-b][1,4]diazepine derivative. Bis(2,5-dihydroisoxazole) is obtained from the reaction of 2a with hydroxylamine hydrochloride, while its reactions with hydrazines afforded the respective 4,5-dihydro-1H-pyrazoles. The target compounds were evaluated as antioxidant and antibacterial agents. The tested compounds showed good to moderate activities compared to ascorbic acid and chloramphenicol, respectively. Full article