title: Discovery of novel 1,2,4-triazol-5-ones as tumor necrosis factor-alpha inhibitors for the treatment of neuropathic pain.
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. ED(50) 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.
authors.affiliation: Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, R.R. District 500078, Andhra Pradesh, India.
authors.forename: Monika
authors.initials: M
authors.lastname: Sharma
authors.forename: Sowmya
authors.initials: S
authors.lastname: Garigipati
authors.forename: Binita
authors.initials: B
authors.lastname: Kundu
authors.forename: Deekshith
authors.initials: D
authors.lastname: Vanamala
authors.forename: Arvind
authors.initials: A
authors.lastname: Semwal
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C045575:1,2,4-triazole