Bioisosteric Replacement of Amide Group with 1,2,3-Triazoles in Acetaminophen Addresses Reactive Oxygen Species-Mediated Hepatotoxic Insult in Wistar Albino Rats.


:Acetaminophen (AP) is a popularly recommended over-the-counter analgesic-antipyretic in clinical use. However, the drug is handicapped by the occurrence of hepatotoxic insult following acute ingestion. Consequently, AP-induced hepatotoxicity is often implicated in accidental or suicidal overdose. In the current study, we investigated the potential of bioisosteric replacement of amide in AP with 1,2,3-triazoles in curbing AP-induced hepatotoxicity. The therapeutic utility of synthesized bioisosteres was established by careful tailoring and optimization of the synthetic methodology along with detailed toxicological testing of pharmacologically potent acetaminophen-triazole derivatives (APTDs). Along the same lines, we herein report a series of 17 novel APTDs synthesized via aromatic substitution using sodium azide, l-proline, and copper iodide followed by click reaction with substituted alkynes using copper sulfate and sodium ascorbate. Pharmacological evaluation of synthesized APTDs revealed that, out of the series of 17 compounds, 5a and 5e were found to be most efficacious in exerting anti-inflammatory, analgesic, and antipyretic activity in an animal model. Further toxicity studies documented that, in both acute and sub-acute toxicology, AP administration caused significant hepatotoxicity, which was found to be a consequence of ROS-mediated oxidative stress. Potent APTDs (5a and 5e), on the other hand, revealed no adverse event in both acute and sub-toxicological analyses. Median lethal dose (LD50) and no observed adverse effect level (NOAEL) values for 5a and 5e were found to be >1000 mg/kg and 2000 mg/kg, respectively. The human equivalent dose, defining the maximum safe concentration of a compound in a human's physiology, was found to be 27.68 mg/kg for the most potent APTDs (5a and 5e). Thus, it can be concluded that triazole incorporation into AP nucleus produced conjugates devoid of hepatotoxic manifestations, having the added advantage of anti-inflammatory efficacy along with analgesic and antipyretic potency.


Chem Res Toxicol


Sahu A,Das D,Sahu P,Mishra S,Sakthivel A,Gajbhiye A,Agrawal R




Has Abstract


2020-02-17 00:00:00












  • Synthesis and monoamine oxidase B catalyzed oxidation of C-4 heteroaromatic substituted 1,2,3,6-tetrahydropyridine derivatives.

    abstract::The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected N-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have le...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Nimkar SK,Anderson AH,Rimoldi JM,Stanton M,Castagnoli KP,Mabic S,Wang YX,Castagnoli N Jr

    更新日期:1996-09-01 00:00:00

  • Synthesis and characterization of bay region halohydrins derived from Benzo[a]pyrene diol epoxide and their role as intermediates in halide-catalyzed cis adduct formation.

    abstract::The bay region epoxide of benzo[a]pyrene (anti-BPDE) alkylates DNA to form adducts with >98% trans stereochemistry. Halide ions catalyze this reaction; however, this pathway is characterized by the formation of adducts with altered cis stereochemistry. Bay region halohydrins are possible intermediates in these reactio...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Song Q,Negrete GR,Wolfe AR,Wang K,Meehan T

    更新日期:1998-09-01 00:00:00

  • Reaction of CO2 with ONOO-: One Molecule of CO2 Is Not Enough.

    abstract::With CO2 present in excess, ONOO- reacts to form an adduct in solution and in the solid state, most likely ONOOCO2-. In solution, the adduct appears within 2 ms and absorbs at 300 with an extinction coefficient, which is either 50% or 100% (preferred) of that of ONOO-, 1.70 × 103 M-1 cm-1, and at 685 nm with an extinc...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Serrano-Luginbuehl S,Kissner R,Koppenol WH

    更新日期:2018-08-20 00:00:00

  • Assessment of DNA Epigenetic Modifications.

    abstract::DNA molecules utilize adenine, thymine, cytosine, and guanine for coding genetic information. In addition to these four canonical nucleobases, DNA molecules also contain a variety of modified nucleobases that can control and regulate gene expression and chromosome structure. Elucidating the functions of DNA modificati...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Yuan BF

    更新日期:2020-03-16 00:00:00

  • Fatty Acid Remodeling of Membrane Glycerophospholipids Induced by Bleomycin and Iron Oxide Nanoparticles in Human Embryonic Kidney Cells.

    abstract::Bleomycin has a long-studied mechanism of action through the formation of a complex with metals, such as iron. The bleomycin-iron complex was recently shown to induce membrane damage by free radical reactivity. Because the use of Fe nanoparticles is spreading for drug delivery strategies, molecular mechanisms of cell ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Krokidis MG,Louka M,Efthimiadou EK,Ferreri C,Chatgilialoglu C

    更新日期:2020-10-19 00:00:00

  • Gamma-radiolysis and hydroxyl radical produce interstrand cross-links in DNA involving thymidine.

    abstract::Interstrand cross-links are minor components of the collection of products formed in DNA by ionizing radiation. Through their formation by other damaging agents, it is known that interstrand cross-links exert significant effects on replication and transcription. The structures of DNA interstrand cross-links produced a...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ding H,Greenberg MM

    更新日期:2007-11-01 00:00:00

  • Molecular recognition between oligopeptides and nucleic acids: DNA binding selectivity of a series of 1,2,4-triazole-containing lexitropsins.

    abstract::The synthesis of a series of 1,2,4-triazole-containing oligopeptide lexitropsins related to the natural antitumor antibiotic distamycin is described. The binding properties of these new agents to both native DNAs and synthetic polydeoxyribonucleotides were determined by UV absorption and circular dichroism studies. Th...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Rao KE,Krowicki K,Burckhardt G,Zimmer C,Lown JW

    更新日期:1991-03-01 00:00:00

  • Unveiling the Variability of "Quartz Hazard" in Light of Recent Toxicological Findings.

    abstract::The variability of quartz hazard stands as one of the most puzzling issues in particle toxicology, notwithstanding the fact that silicosis, the most ancient occupational disease, was the very topic from which the study of the toxicity of particulates developed. Over the years, other adverse effects of silica particles...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Pavan C,Fubini B

    更新日期:2017-01-17 00:00:00

  • Multistage mass spectrometric analysis of human hemoglobin glutathionylation: correlation with cigarette smoking.

    abstract::Protein glutathionylation is an important protein post-translational modification associated with oxidative stress, in which the thiol groups of cysteine residues react with glutathione and form disulfide bonds. Glutathionylation has been shown to affect protein structure and modulate protein function, and is implicat...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Chen HJ,Lin WP,Chiu SD,Fan CH

    更新日期:2014-05-19 00:00:00

  • Chemical reactivity and skin sensitization potential for benzaldehydes: can Schiff base formation explain everything?

    abstract::Skin sensitizers chemically modify skin proteins rendering them immunogenic. Sensitizing chemicals have been divided into applicability domains according to their suspected reaction mechanism. The widely accepted Schiff base applicability domain covers aldehydes and ketones, and detailed structure-activity-modeling fo...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Natsch A,Gfeller H,Haupt T,Brunner G

    更新日期:2012-10-15 00:00:00

  • Influence of glutathione and glutathione S-transferases on DNA interstrand cross-link formation by 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the active anticancer moiety generated by laromustine.

    abstract::Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short-lived (t1/2 ∼ 30 s) chloroethylating agent that can generate high yields of oxophilic electrophiles responsible for the chloroethylation of the O-6 position of guanine ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Penketh PG,Patridge E,Shyam K,Baumann RP,Zhu R,Ishiguro K,Sartorelli AC

    更新日期:2014-08-18 00:00:00

  • Chalcone inhibition of anthracycline secondary alcohol metabolite formation in rabbit and human heart cytosol.

    abstract::Antineoplastic therapy with anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) is limited by the possible development of a dose-related cardiomyopathy. Secondary alcohol metabolites like doxorubicinol (DOXol) and daunorubicinol (DNRol), formed by cytoplasmic two-electron reductases, have been implicated as p...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Silvestrini A,Meucci E,Vitali A,Giardina B,Mordente A

    更新日期:2006-11-01 00:00:00

  • Mutagenic bypass of 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) by DNA polymerase κ in human cells.

    abstract::The formation of 8-oxo-7,8-dihydroguanine (G(O), 8-hydroxyguanine) in DNA and in the nucleotide pool results in G:C→T:A and A:T→C:G substitution mutations, respectively, since G(O) can pair with both C and A. In this study, the role of DNA polymerase κ in the mutagenicity of G(O) was investigated, using a supF shuttle...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Kamiya H,Kurokawa M

    更新日期:2012-08-20 00:00:00

  • Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.

    abstract::In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating g...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ryan PM,Bourdi M,Korrapati MC,Proctor WR,Vasquez RA,Yee SB,Quinn TD,Chakraborty M,Pohl LR

    更新日期:2012-01-13 00:00:00

  • Globin monoadducts and cross-links provide evidence for the presence of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide, chlorothioketene, and 2-chlorothionoacetyl chloride in the circulation in rats administered S-(1,2-dichlorovinyl)-L-cysteine.

    abstract::S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), a mutagenic and nephrotoxic metabolite of trichloroethylene, is bioactivated to S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS) and chlorothioketene and/or 2-chlorothionoacetyl chloride by cysteine conjugate S-oxidase (S-oxidase) and cysteine conjugate beta-lyase (beta-lyase...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Barshteyn N,Elfarra AA

    更新日期:2009-09-01 00:00:00

  • Mechanisms of chlorophyllin anticarcinogenesis against aflatoxin B1: complex formation with the carcinogen.

    abstract::Chlorophyllin (CHL), a food-grade derivative of the green plant pigment chlorophyll, has recently been shown in this laboratory to be a potent inhibitor in vivo of hepatic aflatoxin B1 (AFB1)-DNA adduction and hepatocarcinogenesis (Breinholt et al. (1995) Cancer Res. 55, 57-62). We report here that CHL forms a strong ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Breinholt V,Schimerlik M,Dashwood R,Bailey G

    更新日期:1995-06-01 00:00:00

  • Decomposition rates of isothiocyanate conjugates determine their activity as inhibitors of cytochrome p450 enzymes.

    abstract::Thiol conjugates of isothiocyanates (thiol-ITCs) are metabolites of ITCs formed in the mercapturic acid pathway in mammals. They are effective chemopreventive agents in mouse lung tumor bioassays and in other models. Thiol-ITCs are inhibitors of P450s, but it has not been determined if P450 inhibition is due to conjug...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Conaway CC,Krzeminski J,Amin S,Chung FL

    更新日期:2001-09-01 00:00:00

  • Neuroprotection in the MPTP Parkinsonian C57BL/6 mouse model by a compound isolated from tobacco.

    abstract::Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than in nonsmokers. This evidence, together with the lower levels of brain monoamine oxidase (MAO) activity in smokers and the potential neuroprotective properties of MAO inhibitors, prompted studies which led to the isolation and ch...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Castagnoli KP,Steyn SJ,Petzer JP,Van der Schyf CJ,Castagnoli N Jr

    更新日期:2001-05-01 00:00:00

  • Harmful and beneficial effects of organic monosulfides, disulfides, and polysulfides in animals and humans.

    abstract::Many organic sulfides (mono-, di-, and polysulfides) are present in our environment. Simple derivatives are produced by some plants and animals, while complex sulfides are secondary metabolites of several genera of bacteria and fungi. Sulfides play an important role in the smell and taste of food, and many such compou...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审


    authors: Munday R

    更新日期:2012-01-13 00:00:00

  • Two-Mechanism Model for the Interaction of Etoposide Quinone with Topoisomerase IIα.

    abstract::Topoisomerase II is an essential nuclear enzyme involved in regulating DNA topology to facilitate replication and cell division. Disruption of topoisomerase II function by chemotherapeutic agents is in use as an effective strategy to fight cancer. Etoposide is an anticancer therapeutic that disrupts the catalytic cycl...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Gibson EG,King MM,Mercer SL,Deweese JE

    更新日期:2016-09-19 00:00:00

  • Metabolism of xenobiotic carboxylic acids: focus on coenzyme A conjugation, reactivity, and interference with lipid metabolism.

    abstract::While xenobiotic carboxylic acids (XCAs) have been studied extensively with respect to their enzymatic conversion to potentially reactive acyl glucuronides with implications to drug induced hepatotoxicity, the formation of xenobiotic-S-acyl-CoA thioesters (xenobiotic-CoAs) have been much less studied in spite of data ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审


    authors: Darnell M,Weidolf L

    更新日期:2013-08-19 00:00:00

  • Mass spectrometric characterization of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine N-oxidized metabolites bound at Cys34 of human serum albumin.

    abstract::2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine that is formed during the cooking of meats and poultry. PhIP is a carcinogen in rodents and a potential human carcinogen. Several short-term biomarkers of PhIP have been established for human biomonitoring, but validated long-term ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Peng L,Turesky RJ

    更新日期:2011-11-21 00:00:00

  • Influence of DNA Lesions on Polymerase-Mediated DNA Replication at Single-Molecule Resolution.

    abstract::Faithful replication of DNA is a critical aspect in maintaining genome integrity. DNA polymerases are responsible for replicating DNA, and high-fidelity polymerases do this rapidly and at low error rates. Upon exposure to exogenous or endogenous substances, DNA can become damaged and this can alter the speed and fidel...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审


    authors: Gahlon HL,Romano LJ,Rueda D

    更新日期:2017-11-20 00:00:00

  • In vitro flavon-3-ol oxidation mediated by a B ring hydroxylation pattern.

    abstract::Flavonols are potent naturally occurring antioxidants. Chemical oxidation reactions in combination with modern spectroscopic techniques have been employed to identify oxidized flavonoid products. Although many oxidized derivatives have been generated from commercially available starting materials, few studies have dev...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Krishnamachari V,Levine LH,Zhou C,Paré PW

    更新日期:2004-06-01 00:00:00

  • Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes: energetic and structural relationships to nucleotide excision repair susceptibility.

    abstract::The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B ( Min , J. H. and Pavletich , N. P. ( 2007 ) Nature 449 , 570 - 575 ) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Cai Y,Zheng H,Ding S,Kropachev K,Schwaid AG,Tang Y,Mu H,Wang S,Geacintov NE,Zhang Y,Broyde S

    更新日期:2013-07-15 00:00:00

  • Detection of sodium channel activators by a rapid fluorimetric microplate assay.

    abstract::Marine toxins such as brevetoxins and ciguatoxins are produced by dinoflagellates and can accumulate in seafood. These toxins affect humans through seafood consumption. Intoxication is mainly characterized by gastrointestinal and neurological disorders and, in most severe cases, by cardiovascular problems. To prevent ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Louzao MC,Vieytes MR,Yasumoto T,Botana LM

    更新日期:2004-04-01 00:00:00

  • Identification of Quinone Methide Intermediate Resulting from Metabolic Activation of Icaritin in Vitro and in Vivo.

    abstract::Many herbal medicines such as epimedium have been reported to cause adverse effects, and icaritin is the common aglycone of many glucosides in epimedium. Our present work aimed at the clarification of the metabolic activation of icaritin possibly responsible for the adverse effects of epimedium. A quinone methide meta...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Chen Y,Guo X,Ma Y,Hu X,Peng Y,Zheng J

    更新日期:2019-06-17 00:00:00

  • Role of quinones in toxicology.

    abstract::Quinones represent a class of toxicological intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur t...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审


    authors: Bolton JL,Trush MA,Penning TM,Dryhurst G,Monks TJ

    更新日期:2000-03-01 00:00:00

  • Analysis of butadiene, butadiene monoxide, and butadiene dioxide in blood by gas chromatography/gas chromatography/mass spectroscopy.

    abstract::A new method was developed to quantify the levels of 1,3-butadiene (BD), butadiene monoxide (BDO), and butadiene diepoxide (BDO2) in blood. The method was based on vacuum distillation of tissues followed by analysis of the distillates using multidimensional GC/MS. Metabolites isolated from blood by vacuum distillation...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Bechtold WE,Strunk MR,Thornton-Manning JR,Henderson RF

    更新日期:1995-03-01 00:00:00

  • Radicals derived from histone hydroperoxides damage nucleobases in RNA and DNA.

    abstract::Exposure of individual histone proteins (H1, H2A, H2B, H3, or H4) and histone octamers (consisting of two molecules each of H2A, H2B, H3, and H4) to hydroxyl radicals, generated by gamma-irradiation, in the presence of O(2) generates protein-bound hydroperoxides in a dose-dependent fashion; this is in accord with prev...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Luxford C,Dean RT,Davies MJ

    更新日期:2000-07-01 00:00:00