Abstract:
: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.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Sahu A,Das D,Sahu P,Mishra S,Sakthivel A,Gajbhiye A,Agrawal Rdoi
10.1021/acs.chemrestox.9b00392subject
Has Abstractpub_date
2020-02-17 00:00:00pages
522-535issue
2eissn
0893-228Xissn
1520-5010journal_volume
33pub_type
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