Discovery of Novel 1,2,4-Triazol-5-Ones as Tumor Necrosis Factor-Alpha Inhibitors for the Treatment of Neuropathic Pain

Authors

  • Monika Sharma,

    1. Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India
    Search for more papers by this author
  • Sowmya Garigipati,

    1. Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India
    Search for more papers by this author
  • Binita Kundu,

    1. Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India
    Search for more papers by this author
  • Deekshith Vanamala,

    1. Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India
    Search for more papers by this author
  • Arvind Semwal,

    1. Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India
    Search for more papers by this author
  • Dharmarajan Sriram,

    1. Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India
    Search for more papers by this author
  • Perumal Yogeeswari

    Corresponding authorSearch for more papers by this author

Corresponding authors: Perumal Yogeeswari, pyogee@bits-hyderabad.ac.in, pyogee.sriram@gmail.com

Abstract

In this work, synthetic integration of substituted semicarbazides and various aliphatic, aryl and heteroaryl acids into 1,2,4-triazol-5-ones was accomplished. Following the assessment of neurotoxicity and peripheral analgesic activity, the compounds were evaluated in two peripheral models of neuropathic pain, the chronic constriction injury and partial sciatic nerve ligation to assess their antihyperalgesic and antiallodynic potential. ED50 studies undertaken for selected compounds exhibiting promising efficacies (1c, 3c and 4a) revealed values ranging from 13.21 to 39.85 mg/kg in four behavioral assays of hyperalgesia and allodynia (spontaneous pain, tactile allodynia, cold allodynia, and mechanical hyperalgesia). Mechanistic studies revealed that the compounds suppressed the inflammatory component of the neuropathic pain inhibiting tumor necrosis factor-alpha and preventing oxidative and nitrosative stress.

Ancillary