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Hepatoprotective Bile Acid Co-Drug of Isoniazid: Synthesis, Kinetics and Investigation of Antimycobacterial Potential

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Pharmaceutical Chemistry Journal Aims and scope

The long-course treatment of tuberculosis with isoniazid (INH) leads to hazardous side effects on liver and poor patient compliance. To overcome these toxic effects caused by INH, a unique hepatoprotective co-drug platform was developed by tethering INH with ursodeoxycholic acid (UDCA) – an antioxidant bile acid for possible synergistic outcome. INH and UDCA were linked into co-drug (UI ) through a bioreversible amide linkage by EDCI coupling. UI resisted hydrolysis in acidic (pH 1.2) and basic (pH 7.4) buffers and stomach homogenate of rat, whereas exhibited significant hydrolysis (83.38%) in intestinal homogenate over a period of 6 h. The effect of UI in attenuating oxidative stress and reinstating the normal physiology of liver was striking as it restored the levels of glutathione peroxidase and superoxide dismutase enzymes to normal. Result obtained for antimycobacterial activity assessment clearly demonstrated that UI was as potent as INH in lowering the mycobacterial load in mice. The outcomes of this exploration confirm that the proposed prodrug can add safety as well as efficiency to future medical procedures of tuberculosis management.

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Acknowledgments

The authors would like to thankfully acknowledge Lupin Research Park, Lupin Ltd., Aurangabad, India, for providing the gift sample of isoniazid.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Arvind Gavali College of Pharmacy, Satara, Maharashtra, 415004, India

    Neha V. Bhilare

  2. Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, Maharashtra, 411 038, India

    Neha V. Bhilare & Kakasaheb R. Mahadik

  3. Amity Institute of Pharmacy, Amity University Uttar Pradesh, Gomti Nagar Extn, Lucknow, 226028, India

    Suneela S. Dhaneshwar

  4. Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, Uttar Pradesh, 226021, India

    Arunava Dasgupta

  5. Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, Maharashtra, 411 038, India

    Tejal Zende & Siddhart Kapoor

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  1. Neha V. Bhilare
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Correspondence to Suneela S. Dhaneshwar.

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Bhilare, N.V., Dhaneshwar, S.S., Mahadik, K.R. et al. Hepatoprotective Bile Acid Co-Drug of Isoniazid: Synthesis, Kinetics and Investigation of Antimycobacterial Potential. Pharm Chem J 54, 678–688 (2020). https://doi.org/10.1007/s11094-020-02256-1

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