Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 27, 2018; 10(7): 496-508
Published online Jul 27, 2018. doi: 10.4254/wjh.v10.i7.496
Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation
Neha Vithal Bhilare, Suneela Sunil Dhaneshwar, Kakasaheb Ramoo Mahadik
Neha Vithal Bhilare, Suneela Sunil Dhaneshwar, Kakasaheb Ramoo Mahadik, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
Author contributions: Bhilare NV and Dhaneshwar SS equally contributed to the conception and design of the study, the acquisition, analysis and interpretation of the data, and drafted the article and made revisions related to the intellectual content of the manuscript; Mahadik KR performed critical revision of the manuscript and approved the final version of the article to be published.
Institutional review board statement: No humans were used in this study and IRB approval was not required.
Institutional animal care and use committee statement: All animal experimentation was approved by the Institutional Animal Ethics Committee (IAEC-approval number: CPCSEA/PCH/02/2016-17) of Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune- 411038, India.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: There are no additional data available in relation to this manuscript.
ARRIVE guidelines statement: The ARRIVE guidelines have been adopted in the study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Suneela Sunil Dhaneshwar, PhD, Professor, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Maharashtra 411038, India. suneeladhaneshwar@rediffmail.com
Telephone: +91-20-25437237 Fax: +91-20-25439382
Received: March 11, 2018
Peer-review started: March 12, 2018
First decision: March 29, 2018
Revised: April 6, 2018
Accepted: April 9, 2018
Article in press: April 9, 2018
Published online: July 27, 2018
Abstract
AIM

To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid (INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.

METHODS

INH was conjugated with N-acetyl cysteine (NAC) and N-(2)-mercaptopropionyl glycine using the Schotten-Baumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.

RESULTS

Prodrugs were found to be stable in acidic (pH 1.2) and basic (pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly (59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially.

CONCLUSION

The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.

Keywords: Aminothiols, Antioxidants, N-acetyl cysteine, N-(2-mercaptopropionyl) glycine, Isoniazid, L-methionine, Liver injury, Tuberculosis

Core tip: To overcome the deleterious effects caused by long-term use of isoniazid (INH), a novel hepatoprotective prodrug strategy was developed by integrating the antioxidant property of aminothiols with INH moiety to improve its therapeutic safety. The anticipated prodrugs were synthesized using facile method of synthesis, wherein aminothiols were tethered to the INH molecule via biocleavable amide linkage. Upon hepatoprotective potential assessment, the prodrug NI displayed noteworthy effects, whereas prodrugs MGI and MI exhibited moderate effects. The findings of this study strongly suggest that concept-based design of hepatoprotective prodrugs can be applied effectively in reversing toxic effects of INH and its metabolites on liver.