Synthesis and evaluation of paracetamol alkyl derivatives to reduce hepatotoxicity.
Journal name: World Journal of Pharmaceutical Research
Original article title: Synthesis and bioevaluation of alkyl derivatives and prodrug of paracetamol to reduce hepatotoxicity
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Shalini Kesharwani, Dr. Arun Patel, Shailendra Patel and Neelesh Dwivedi
World Journal of Pharmaceutical Research:
(An ISO 9001:2015 Certified International Journal)
Full text available for: Synthesis and bioevaluation of alkyl derivatives and prodrug of paracetamol to reduce hepatotoxicity
Source type: An International Peer Reviewed Journal for Pharmaceutical and Medical and Scientific Research
Doi: 10.20959/wjpr202013-18941
Copyright (license): WJPR: All rights reserved
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Summary of article contents:
Introduction
Paracetamol is a widely used analgesic and antipyretic drug known for its effectiveness in pain relief and fever reduction. However, its usage is associated with substantial risks, particularly hepatotoxicity, due to its metabolites, specifically N-acetyl-p-benzoquinoneimine (NAPQI). This toxicity primarily occurs when paracetamol is taken in excessive doses, which leads to liver damage and potentially fatal outcomes. The study undertaken by Kesharwani et al. focuses on synthesizing alkyl derivatives and prodrugs of paracetamol in a bid to reduce these harmful effects while maintaining its therapeutic efficacy.
Alkyl Derivatives and Their Effects on Hepatotoxicity
Kesharwani's research involves the creation of alkyl derivatives of paracetamol by substituting alkyl groups on the N-position of the compound. Although these derivatives exhibit antipyretic activity, they also retain significant hepatotoxic potential, indicating a trade-off between effectiveness and safety. Experimental evaluations showed that the derivatives with methyl (CH₃) and ethyl (C₂H₅) groups maintain pharmacological activity similar to paracetamol but do not substantially mitigate hepatotoxic outcomes. This highlights the importance of structure-activity relationships in drug design, particularly in tweaking compound structures to balance therapeutic benefits against adverse effects.
Prodrugs with Amino Acids as Precursors of Glutathione
The study further explores the synthesis of prodrugs incorporating amino acids such as N-acetylcysteine, cysteine, and methionine—known precursors to glutathione, a natural antioxidant. These prodrugs were designed to enhance the body's protective mechanisms against potential toxicity associated with paracetamol metabolism. The experimental results indicated that these prodrugs exhibited considerable antipyretic activity while demonstrating markedly lower hepatotoxic potential compared to unmodified paracetamol. This demonstrates a promising avenue for drug development focused on improving safety profiles through the incorporation of biologically relevant molecules.
Pharmacological Evaluation and Antipyretic Activity
The pharmacological evaluation of the synthesized compounds was conducted using an antipyretic study, where multiple synthesized compounds were tested for their capacity to reduce fever induced by Brewer’s yeast in Wistar rats. All synthesized compounds were found to exhibit antipyretic effects; however, their relative effectiveness varied. Notably, compounds PD-3, PD-4, and PD-5 showed significant antipyretic activity, suggesting that structural modifications can enhance therapeutic efficacy. However, the study also emphasized the need to consider the hepatotoxicity of these compounds, suggesting that these derivatives could require careful dosage adjustments or further refinements before clinical use.
Conclusion
In conclusion, the research presented by Kesharwani et al. underscores the dual challenge of maintaining the therapeutic efficacy of paracetamol while minimizing hepatotoxicity. The synthesis of both alkyl derivatives and prodrugs indicates potential pathways for achieving safer analgesic and antipyretic drugs, particularly through the incorporation of amino acid precursors that bolster the body's natural defenses. The findings highlight a continuum in drug development where structural modifications can enhance therapeutic profiles while addressing safety concerns, ultimately aiming for more effective and safer healthcare solutions.
FAQ section (important questions/answers):
What is the main focus of the research conducted by Kesharwani et al.?
The research focuses on synthesizing alkyl derivatives and prodrugs of paracetamol to reduce its hepatotoxicity while maintaining or improving its analgesic and antipyretic effects.
What causes paracetamol's hepatotoxicity according to the study?
Paracetamol's hepatotoxicity is primarily due to its metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which depletes glutathione, leading to cellular damage in the liver.
What were the synthesized compounds tested for in this research?
The synthesized compounds were evaluated for their antipyretic activity and hepatotoxic potential using various biochemical and morphological parameters on an animal model.
How was the antipyretic activity of compounds measured?
Antipyretic activity was evaluated using the Brewer's yeast-induced pyrexia method on Wistar rats, comparing the effectiveness of synthesized compounds with paracetamol.
Which synthesized compounds showed the least hepatotoxicity?
Compounds PD-3, PD-4, and PD-5 exhibited significant antipyretic activity and demonstrated lower hepatotoxicity compared to paracetamol and other derivatives.
What methods were used to confirm the structures of synthesized compounds?
The purity and structure of the synthesized compounds were confirmed using thin-layer chromatography (TLC) and melting point analysis in conjunction with IR and 1H NMR spectroscopy.
Glossary definitions and references:
Scientific and Ayurvedic Glossary list for “Synthesis and evaluation of paracetamol alkyl derivatives to reduce hepatotoxicity.”. This list explains important keywords that occur in this article and links it to the glossary for a better understanding of that concept in the context of Ayurveda and other topics.
1) Activity:
Activity refers to the efficacy of the synthesized compounds in exerting antipyretic effects, which is essential when evaluating new pharmaceuticals. The study shows that different derivatives of paracetamol demonstrated varying levels of antipyretic activity, highlighting effectiveness as a key comparison with standard paracetamol for therapeutic purposes.
2) Drug:
A drug is a substance used for medical treatment, and in this research, paracetamol is the primary drug under investigation. The goal is to develop derivatives that enhance its therapeutic effects while minimizing side effects, such as hepatotoxicity, making drug development critical in pharmaceutical research.
3) Toxicity:
Toxicity evaluates the harmful effects a substance can have on an organism. In this study, attention is focused on the hepatotoxic potential of paracetamol and its derivatives. Understanding the toxicity levels of synthesized compounds helps in assessing their safety for therapeutic use, especially before clinical approvals.
4) Table:
Table organization is crucial for summarizing data effectively. In the study, tables present synthesis yields, melting points, and the antipyretic effects of synthesized compounds in a clear format, enabling researchers to compare results easily and draw meaningful insights about the efficacy and safety of each compound.
5) Jabalpur:
Jabalpur is the location of the Shri Ram Group of Institutions where the research is conducted. The geographical affiliation underscores the academic and research capabilities available within this region, contributing to advances in pharmaceutical sciences and providing a context for the developmental work on paracetamol derivatives.
6) Patel:
Patel refers to one of the authors involved in the research study. The contributions of the researchers, including Patel, are vital as they bring expertise and collaborative effort in synthesizing new compounds. Recognition of individual researchers is important for accountability and academic acknowledgment in scientific literature.
7) Blood:
Blood is a vital fluid in the body that circulates nutrients and carries waste materials. In the context of this research, blood parameters such as SGPT, SGOT, and SALP are evaluated to assess the hepatotoxicity of synthesized compounds, indicating the health of liver function in the animal models used.
8) Study (Studying):
The study represents a systematic investigation into the creation and evaluation of new paracetamol derivatives. It encompasses both the synthesis and bioevaluation processes to determine the efficacy, safety, and pharmacological profiles of compounds, reinforcing the need for rigorous testing in pharmaceutical development.
9) Shri (Sri, Sr):
Shri is a title used as a sign of respect in India, belonging to the institutions and their faculty. It establishes a formal context in which the research is conducted within a recognized academic framework, highlighting the institutional support for scientific investigation and collaboration among researchers.
10) Pharmacological:
Pharmacological relates to the study of drug action within the body. Understanding pharmacological properties of compounds, such as their antipyretic and hepatotoxic effects, is paramount for developing effective medications. This research's aim is to uncover better pharmacological profiles of paracetamol derivatives compared to existing treatments.
11) Accumulation (Accumulating, Accumulate):
Accumulation refers to the build-up of harmful substances like N-acetyl-p-benzoquinoneimine (NAPQI) due to paracetamol metabolism. This process is directly linked to hepatotoxicity, making it crucial to study how new derivatives might minimize harmful accumulation, improving patient safety, and drug efficacy in managing pain and fever.
12) Shailendra (Sailendra, Shaila-indra, Shailemdra):
Shailendra denotes another author of the research, contributing to the collaborative effort in studying paracetamol derivatives. Acknowledging each author's involvement enhances the research's credibility, highlighting teamwork and the diverse expertise needed to explore complex pharmaceutical issues in drug development.
13) Observing:
Observing involves the careful monitoring of experimental data and outcomes during the research. This term underscores the importance of empirical analysis, as researchers must meticulously observe the pharmacological effects and toxicity levels of synthesized compounds to ensure accurate and reliable findings that inform future applications.
14) Purity:
Purity refers to the degree to which a substance is free from contaminants. The synthesis of new pharmaceutical compounds necessitates an assessment of their purity to ensure the safety and effectiveness of the drug. In this study, techniques like TLC and melting point determination are employed for verification.
15) Animal:
Animal represents the test subjects used in pharmacological evaluations within the study. Wistar rats are commonly used in toxicity testing to understand how synthesized compounds may affect liver function and overall health, bridging the gap between laboratory research and potential clinical applications in humans.
16) Water:
Water is a solvent often utilized in scientific studies and assays. In this research, the solubility of synthesized compounds in water and other solvents is assessed to determine their feasibility for formulation and administration, which is critical in developing effective and safe pharmaceutical products.
17) Death:
Death signifies the ultimate consequence of severe toxicity or overdose in pharmacological contexts. This research aims to mitigate potential risks associated with paracetamol-related hepatotoxicity by developing derivatives that lower harmful metabolite levels and therefore reduce the risk of fatal outcomes associated with overdose situations.
18) Life:
Life represents the overall goal of pharmaceutical research: preserving and improving human health. By developing safer paracetamol derivatives with reduced hepatotoxicity, the researchers aim to enhance therapeutic options available to patients and contribute to the quality of life through better medication management.
Other Science Concepts:
Discover the significance of concepts within the article: ‘Synthesis and evaluation of paracetamol alkyl derivatives to reduce hepatotoxicity.’. Further sources in the context of Science might help you critically compare this page with similair documents:
Pharmacological evaluation, TLC, Drug discovery, Physicochemical properties, Amino acid, Antipyretic activity, SGOT, SGPT, Glutathione, N-acetylcysteine, Prodrug, Methionine, Cysteine, Biochemical parameter, Morphological parameters, Histopathological parameter.