Acetaminophen Derivatives Research Articles

Repurposing Synthetic Acetaminophen Derivatives Containing a Benzothiazole Scaffold as an Alternative Therapy for Infectious Diarrhea Caused by Drug-Resistant Shigella Species

Repurposing Synthetic Acetaminophen Derivatives Containing a Benzothiazole Scaffold as an Alternative Therapy for Infectious Diarrhea Caused by Drug-Resistant Shigella Species

Physicochemical properties and cytochromes P-450 kinetics of a trifluoroacetamido derivative of acetaminophen

Acetaminophen (N-acetyl-para-aminophenol, APAP) is a commonly used analgesic and antipyretic drug. While acetaminophen is generally safe when taken at therapeutic doses, it causes severe liver and kidney damage at overdose quantities. Cytochromes P-450 (CYP) catalyze the transformation of APAP to N-acetyl-p-benzoquinone imine (NPAQI), a toxic metabolite. The quinone imine moiety of NAPQI reacts with the thiol side chain of glutathione (GSH). High concentrations of NAPQI rapidly deplete cells of GSH resulting in cell death. The introduction of a trifluoromethyl group to APAP would be expected to change the physicochemical properties as well as the kinetics of CYP catalysis of the fluorinated derivative in comparison to APAP. Relative to APAP, 4-triflouroacetamidophenol (3F-APAP) is slightly more acidic and significantly more lipophilic. Using Sprague Dawley rat liver microsomes, it was observed that APAP and 3F-APAP have similar binding affinity for the CYP proteome; however, 3F-APAP undergoes catalysis by the CYP proteome at half the rate as that of APAP. This decreased rate of CYP catalysis for 3F-APAP would be expected to result in it being less hepatotoxic relative to APAP.

Electrochemistry of Selected Acetaminophen Derivatives

Acetaminophen (N-(4-hydroxyphenyl)acetamide, APAP) belongs to the most frequently used pharmaceuticals with analgesic and antipyretic effect [1]. The metabolization of APAP via oxidation pathway lead to formation of highly reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI). It immediately reacts with a nucleophile e.g. with glutathione by formation of respective conjugate. The level of such conjugates can be directly linked to the toxicity of APAP in humans.Hence, three derivatives of acetaminophen were synthesized and characterized [2]. In this contribution, we focus on the characterization of redox properties of selected acetaminophen derivatives (see scheme 1) which were studied by means of cyclic voltammetry, rotating-disk voltammetry and UV-VIS absorption spectrometry. The oxidation mechanism was studied in phosphate buffers of different pH as well as in non-aqueous environment of N,N-dimethylformamide The influence of substituents on the electron transfer mechanism was estimated and corresponding rate constants were evaluated. We found that the protonation/deprotonation of acetaminophen derivatives act as a rate determining steps in aqueous media. The obtained electrochemical results were accompanied by chemical ones using reaction of the conjugates with diphenylpicrylhydrazyl (DPPH radical assay) in order to examine their interaction with radical, hence radical scavenging ability. Acknowledgement This work was supported by the Czech Science Foundation (GA19-11867S). References L. O. Boreus, F. Sandberg, Acta physiologica Scandinavica 1953, 28, 261-265.J. Vanova, D. Malinak, R. Andrys, M. Kubat, T. Mikysek, E. Rousarova, K. Musilek, T. Rousar, P. Cesla, J. Chromatogr. A 2022, 1669, 11. Figure 1

Boronate-Based Oxidant-Responsive Derivatives of Acetaminophen as Proinhibitors of Myeloperoxidase.

Myeloperoxidase (MPO) is an important component of the human innate immune system and the main source of a strong oxidizing and chlorinating species, hypochlorous acid (HOCl). Inadvertent, misplaced, or excessive generation of HOCl by MPO is associated with multiple human inflammatory diseases. Therefore, there is a considerable interest in the development of MPO inhibitors. Here, we report the synthesis and characterization of a boronobenzyl derivative of acetaminophen (AMBB), which can function as a proinhibitor of MPO and release acetaminophen, the inhibitor of chlorination cycle of MPO, in the presence of inflammatory oxidants, i.e., hydrogen peroxide, hypochlorous acid, or peroxynitrite. We demonstrate that the AMBB proinhibitor undergoes conversion to acetaminophen by all three oxidants, with the involvement of the primary phenolic product intermediate, with relatively long half-life at pH 7.4. The determined rate constants of the reaction of the AMBB proinhibitor with hydrogen peroxide, hypochlorous acid, or peroxynitrite are equal to 1.67, 1.6 × 104, and 1.0 × 106 M-1 s-1, respectively. AMBB showed lower MPO inhibitory activity (IC50 > 0.3 mM) than acetaminophen (IC50 = 0.14 mM) toward MPO-dependent HOCl generation. Finally, based on the determined reaction kinetics and the observed inhibitory effects of two plasma components, uric acid and albumin, on the extent of AMBB oxidation by ONOO- and HOCl, we conclude that ONOO- is the most likely potential activator of AMBB in human plasma.

Synthesis and Characterization of New Functionalized 1,2,3-Triazole-Based Acetaminophen Derivatives via Click Chemistry from Expired Commercial Acetaminophen Tablets

We hereby describe an efficient method for the preparation of a series of new 1-substituted 1,2,3-triazole-based acetaminophen derivatives through a clean, good-yielding, simple, and expeditious procedure based on the O-propargylation reaction of the acetaminophen (APAP) obtained from expired commercial tablets and the CuBr(PPh3)3-catalyzed Huisgen reaction between O-propargylated APAP and diverse organoazides prepared from commercially available anilines as available starting reagents. An interesting nitric oxide-releasing 1,2,3-triazole hybrid of APAP was also obtained easily using the developed method. The structures of the designed hybrid compounds, which are expected to be pharmacologically active, were characterized by FT-IR, 1H-, and 13C-NMR and are reported for the first time. According to the in-silico ADMET prediction studies performed in this work and literature analysis, these hybrids are interesting models in search of new pharmacological nontoxic agents endowed with anti-inflammatory and anticancer properties.

Synthesis, characteristic fragmentation patterns, and antibacterial activity of new azo compounds from the coupling reaction of diazobenzothiazole ions and acetaminophen

Abstract In this study, a series of azobenzothiazole dyes 4 were synthesized via diazotization of substituted benzothiazole derivatives followed by azo coupling with acetaminophen. The chemical structures of all synthesized compounds were confirmed using analytical data and spectroscopic techniques, including UV-visible, IR, mass spectra, and 1H- and 13C-NMR. The in situ formed diazobenzothiazole ions regiospecifically react with acetaminophen derivatives in the Hollemann-guided electrophilic aromatic substitution mechanism. The regio-orientations were established, on the one hand, by a rigorous interpretation of 1H-NMR spectra and, on the other hand, by the characteristic fragmentation patterns observed on the electrospray mass spectra. In the cases of 4a and 4b, multisubstitutions occurred. The antimicrobial activity of compound 4, along with all the starting materials, was investigated on Pseudomonas aeruginosa PA01, Staphylococcus aureus 18, Escherichia coli 64R, and S. aureus ATCC 25923. The results showed that this skeletal framework exhibited marked potency as antibacterial agents. The most active antibacterial agent against both targeted organisms was compound 4a′.

N-[7-Chloro-4-[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]quinoline]-acetamide

The 1,2,3-triazole is a well-known biologically active pharmacophore constructed by the copper-catalyzed azide–alkyne cycloaddition. We herein reported the synthesis of 4-amino-7-chloro-based [1,2,3]-triazole hybrids via Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of 4-azido-7-chloroquinoline with an alkyne derivative of acetaminophen. The compound was fully characterized by Fourier-transform infrared (FTIR), proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR), heteronuclear single quantum coherence (HSQC), ultraviolet (UV) and high-resolution mass spectroscopies (HRMS). This compound was screened in vitro with different normal and cancer cell lines. The drug likeness of the compound was also investigated by predicting its pharmacokinetic properties.

Experience of using a complex bioregulatory drug in young children

Introduction. The paper presents modern insights into the pathogenesis and role of inflammatory reactions in the developmentof the respiratory pathology. The safety and high potential of the use of complex bioregulatory drugs as elements of pathogenetic and symptomatic therapy of the respiratory diseases have been substantiated. The authors present the results of their own clinical observations on the use of a complex bioregulatory drug as an anti-inflammatory agent to treat acute respiratory diseases in young children.Clinical case 1. The observation included 102 children aged 1 to 3 years with the symptoms of acute respiratory viral infection, who underwent outpatient treatment. 53 children of them received a complex bioregulatory drug as a symptomatic antiinflammatory and antipyretic therapy according to the treatment regimen set out in the patient information leaflet. The comparison group consisted of 49 children, who received acetaminophen derivatives to relieve the similar symptoms at least once per day. The findings showed that the bioregulatory drug, when used according to the treatment regimen, effectively relieved the symptoms of fever in 46 children (87%), the same indicator in the comparison group was 44 children (89%) (p > 0.05%).Clinical case 2.We observed 26 children aged 9 to 18 months with teething syndrome, which was treated with a bioregulatory drug as a symptomatic therapy. The therapy lasted 3 to 7 days. The results showed that the bioregulatory drug effectively relieved the whole complex of teething symptoms.Сonclusion. Viburcol has been shown to be highly effective as an antipyretic agent, as well as a drug to relieve symptoms during teething. No children who used the drug showed side effects. The authors advise the widespread use of complex bioregulatory drugs in routine paediatric practice.

Bioactive acetaminophen derivatives from Penicillum herquei JX4

Two novel epimer pairs of acetaminophen derivatives penicilquei A-D (1–4) were isolated from Penicillium herquei JX4. Their structures were elucidated using comprehensive spectroscopic methods. The absolute configurations of penicilquei A-D (1–4) were determined by modifified Mosher's method, and comparing their experimental and calculated electronic circular dichroism (ECD) spectra. Penicilquei A-D (1–4) are the first example of acetaminophen derivatives featuring an unprecedented carbon skeleton. The inhibitory activities of all compounds against nine phytopathogenic fungi and α-glucosidase were evaluated. Penicilquei A-D (1–4) showed strong inhibitory activities against at least eight phytopathogenic fungus.

Facile and clean electrochemical synthesis of new acetaminophen derivatives through electrochemical oxidation of acetaminophen in the presence of thiouracil derivatives

ABSTRACTThe electrochemical oxidation of acetaminophen (1a) is carried out in the presence of thiouracil derivatives (3a–c), as nucleophiles, in an acetate buffer solution (0.15 M, pH 5) mixed with Dimethylformamide (DMF) using cyclic voltammetry and coulometry under a constant potential. The results obtained indicate that N-acetyl-p-benzoquinone-imine derived from acetaminophen participates in a 1,4-Michael-type addition reaction with thiouracils to form the corresponding acetaminophen derivatives (4a–c) in good yields and with high purities using a facile, catalyst-free, and one-pot electrochemical method using three carbon electrodes in an undivided cell under mild conditions. The products obtained were characterized after purification by IR, 1H NMR, and 13C NMR spectroscopies, and by the elemental analysis method.

Synthesis of 4-((5-acetamido-2-hydroxyphenyl) diazenyl) benzenesulfonic, a Azobenzene Derivative of the Acetaminophen, and Evaluation its Potential as a pH Value Indicator

Strong absorption and bright colours of the azobenzene have attracted attention for the development of chemical sensors of this class of compounds, such as acid-base indicators. The present work describes the synthesis of a derivative of the drug acetaminophen, the azobenzene 4 - ((5-acetamido-2-hydroxyphenyl) diazenil) benzenesulfonic, and evaluation of the potential of this as a pH value indicator. The azobenzene was obtained in 77% yield and low cost, and shown to be a promising pH value indicator with good solubility in water, readily distinguishable color change in the zone turning, wide range of usable concentration and pK a values calculated: 9,072; 9,322 e 9,265. Thus it can be used as pH value indicator of basic band, and the results may contribute to the development of new synthetic compounds with acid-base indicator activity with low production cost.

Micellar Effects upon the Alkaline Hydrolysis of Acetaminophen Prodrugs: Carboxylic and Carbonic Acid Esters

The rates of alkaline hydrolysis for four carboxylate esters (4-acetaminophenyl acetate, 4-acetaminophenyl butyrate, 4-acetaminophenyl heptanoate and 4-acetaminophenyl benzoate) and three carbonate ester (4-acetaminophenyl methylcarbonate, 4-acetaminophenyl ethylcarbonates and 4-acetaminophenyl propylcarbonates) prodrugs of acetaminophen derivatives were determined in aqueous and micellar media. The cationic micelles of cetyltrimethylammonium bromide (CTABr) and cetyltrimethylammonium sulfate [(CTA)2SO4] catalyzed the rate of the reaction. The anionic sodium dodecyl sulphate (SDS) and non-ionic Brij-35 surfactants inhibited the rate of the reaction. Added salt did not influence the rate of the reaction in the aqueous medium but decreased the values of observed rate constant in the micellar media. The rate enhancement in cationic micelles was treated by applying the pseudophase ion exchange model while the inhibition effect on the rate of hydrolysis was described using the Poisson–Boltzman pseudophase model. The binding constant (K s ) for the acetaminophen derivatives increased with increasing hydrocarbon chain length while the values of micellar rate constant (k m ) decreased with the increase in chain length. The increase in values of K s and decrease in k m are ascribed to the hydrophobic interaction between the acetaminophen derivative and surfactant molecule and molecular orientation of the substrate in the micelles.

A Green Electrochemical Method for the Synthesis of Acetaminophen Derivatives

Electrochemical synthesis of new acetaminophen derivatives (4a-4c) has been carried out by the electrochemical oxidation of acetaminophen, N-(4-hydroxyphenyl)acetamide, in the presence of arylsulfinic acids (3a-3c) as nucleophiles in aqueous solution using cyclic voltammetry. The results revealed that the electrochemically generated N-acetyl-p-benzoquinone-imine (2) participates in Michael type addition reaction with arylsulfinic acids via an EC mechanism and is converted to the acetaminophen derivatives (4a-4c). The present work has led to the development of a facile and environmentally friendly reagent-less electrochemical method with high atom economy and safe waste under green conditions.

ChemInform Abstract: Synthesis of a Novel Water Soluble Phthalimide Derivative of Acetaminophen as Potential Analgesic and Antipyretic Agent.

A short process for the preparation of water soluble, potential analgesic compound, N-[(4-hydroxy-phenylcarbamoyl)-methyl]phthalamic acid 4 has been developed. Two synthetic routes (A and B) have been established for the preparation of 2-(1,3-dioxo1,3-dihydro-isoindol-2-yl)-N-(4-hydroxyphenyl)acetamide 3. In route A, 4-aminophenol 5 is reacted with chloroacetyl chloride 6 in solution of potassium acetate and acetic acid at 0-5°C to yield N-(4-hydroxyphenyl)-2-chloroacetamide 7. The latter is reacted with potassium phthalimide 8 and KI in DMF at 130°C to give 3. Alternatively, in route B, reaction of phthalic anhydride 8 with glycine 9 at 150°C yields the acid intermediate (1,3-dioxo-1,3dihydro-isoindol-2-yl)-acetic acid 11, which on reaction with 4aminophenol 6 in DMF and in the presence of dicyclohexylcarbodimide gives 3. The latter is hydrolysed in ethanolic KOH to afford 4.

Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice

It is now believed that cancer stem cells (CSCs) that are resistant to chemotherapy due to their undifferentiated nature drive tumor growth, metastasis and relapse, so development of drugs that induce differentiation of CSCs should have a profound impact on cancer eradication. In this study, we screened medicines that are already in clinical use for drugs that induce differentiation of CSCs. We used MDA-MB-231, a human breast cancer cell line that contains cancer stem cell-like cells. We found that acetaminophen, an anti-inflammatory, antipyretic and analgesic drug, induces differentiation of MDA-MB-231 cells. Differentiation was assessed by observing alterations in cell shape and expression of differentiated and undifferentiated cell markers, a decrease in cell invasion activity and an increase in susceptibility to anti-tumor drugs. This increased susceptibility seems to involve suppression of expression of multidrug efflux pumps. We also suggest that this induction of differentiation is mediated by inhibition of a Wnt/β-catenin canonical signaling pathway. Treatment of MDA-MB-231 cells with acetaminophen in vitro resulted in the loss of their tumorigenic ability in nude mice. Furthermore, administration of acetaminophen inhibited the growth of tumor xenografts of MDA-MB-231 cells in both the presence and absence of simultaneous administration of doxorubicine, a typical anti-tumor drug for breast cancer. Analysis with various acetaminophen derivatives revealed that o-acetamidophenol has a similar differentiation-inducing activity and a similar inhibitory effect on tumor xenograft growth. These results suggest that acetaminophen may be beneficial for breast cancer chemotherapy by inducing the differentiation of CSCs.

Notice of Retraction: ‘A NO‐releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway’ (Br J Pharmacol 135; 589–599; 2002)

Notice of Retraction: ‘A NO‐releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway’ (<i>Br J Pharmacol</i> 135; 589–599; 2002)

New Synthesis of Acetaminophen Derivatives Containing a Phosphorus Atom.

Two derivatives of acetaminophen have been efficiently prepared from 4-aminophenol via a two-step procedure involving acetylation of OH and NH 2 groups and then the reaction of the acetylated compounds with diakyl acetylenedicarboxylate in the presence of triphenylphosphine. The products were obtained in good yields.

HPLC Determination of Acetaminophen in Saliva Based on Precolumn Fluorescence Derivatization with 12-(3,5-Dichloro-2,4,6-triazinyl)-benzo[d]benzo[1′,2′-6,5]isoindolo[1,2-b][1,3]thiazolidine

A high-performance liquid-chromatographic method for the determination of acetaminophen in saliva has been developed. This method is based on the precolumn derivatization of acetaminophen with 12-(3,5-dichloro-2,4,6-triazinyl)benzo[d]benzo[1',2'-6,5]isoindolo[1,2-b][1,3]thiazolidine, a new fluorescence derivatization reagent for phenolic compounds. The resulting derivative of acetaminophen is separated by isocratic elution on a reversed-phase column, and is fluorometrically detected at an emission wavelength of 560 nm with an excitation wavelength of 540 nm. The detection limit (signal-to-noise ratio = 3) was 0.1 microg/mL in saliva. The proposed method permits a highly sensitive and simple determination of acetaminophen in a small amount of saliva without any sample purification.

New Synthesis of Acetaminophen Derivatives Containing a Phosphorus Atom

Two derivatives of acetaminophen have been efficiently prepared from 4-aminophenol via a two-step procedure involving acetylation of OH and NH 2 groups and then the reaction of the acetylated compounds with diakyl acetylenedicarboxylate in the presence of triphenylphosphine. The products were obtained in good yields.

Acetaminophen hepatotoxicity: NO to the rescue.

Severe liver injury as a result of overdose or chronic use of acetaminophen (paracetamol) remains a significant clinical problem, accounting for as much as 40% of cases of acute liver failure. The mechanisms underlying the liver injury caused by acetaminophen have become much better understood in recent years. In this issue, Fiorucci et al. report that delivery of nitric oxide (NO) in small amounts to the liver, via a novel derivative of the bile acid ursodeoxycholic acid, results in significant protection of the liver from acetaminophen-induced damage. NO appears to produce these beneficial actions through several mechanisms, including the suppression of synthesis of several proinflammatory cytokines. There is also substantial evidence that a NO-releasing derivative of acetaminophen offers several advantages over acetaminophen itself, including enhanced analgesic potency and reduced liver toxicity.