Discovery of Fused Triazolo-thiadiazoles as Inhibitors of TNF-alpha: Pharmacophore Hybridization for Treatment of Neuropathic Pain

INTRODUCTION: Neuropathic pain is a complex, chronic pain state that is usually accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional, or injured. METHODS: A series of pharmacophoric hybrids of substituted aryl semicarbazides incorporated into a fused triazolo-thiadiazole nucleus were synthesized and evaluated for neuropathic pain activity. After the assessment of neurotoxicity and peripheral analgesic activity, the compounds were evaluated in two peripheral neuropathic pain models, the chronic constriction injury and partial sciatic nerve ligation, to assess their antiallodynic and antihyperalgesic potential. RESULTS: Selected compounds exhibiting promising efficacies (4b, 6a, and 7e) revealed median effective dose (ED(50)) values ranging from 7.62–28.71 mg/kg in four behavioral assays of allodynia and hyperalgesia (spontaneous pain, tactile allodynia, cold allodynia, and mechanical hyperalgesia). Studies carried out to assess the underlying mechanism revealed that compounds suppressed the inflammatory component of the neuropathic pain by inhibiting tumor necrosis factor (TNF)-alpha and preventing oxidative and nitrosative stress. CONCLUSION: Using a hybrid design approach, the present study identified novel chemical compounds that could be a potential lead for the treatment of neuropathic pain.