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.

A structural analysis of 2,5‐diaryl‐4H‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones: NMR in the solid state, X‐ray crystallography, and GIPAW calculations

“…Remarkably, the C-6 0 (6) presents the highest deviation, mostly due to the commented disorder of the fluorine atoms in the crystal structure. Nevertheless, the computed mean absolute error (MAE) is acceptable in all three cases, 3.0 (3), 2.7 (5), and 2.8 (6), indicating that the GIPAW method satisfactorily reproduces the experimental chemical shifts of 3, 5, and 6 in solid state. [42] 3 | EXPERIMENTAL…”

“…Due to its biological properties, many other triazol-3-ones, not necessarily having a 2,5-diaryl pattern, have previously been described; they are Ca 2+ conductance openers activated potassium channels, [2] antimicrobials, [3] antifungals, [4,5] TNF-α inhibitors, [6] selective CB1 receptor antagonists, [7] angiotensin II AT1 receptor antagonists, [8,9] antioxidants, [10] and AChE inhibitors. [11] A thorough understanding of biological properties requires information about the structure of molecules, among them tautomerism [1] and conformational isomerism.…”

Renin–angiotensin system in pain: Existing in a double life?

“…The role of TNF-α and other cytokines in development of peripheral as well as central sensitization in neuropathic pain is very well documented. 45,46 The up-regulation of TNF-α has been detected at the injury site, mainly in the macrophages and Schwann cells. 47,48 Nerve biopsies from patients with painful neuropathy also show higher levels of TNF-α expression, especially in the Schwann cells.…”

Hypervalent‐Iodine(III)‐Mediated Oxidative Methodology for the Synthesis of Fused Triazoles

“…[64] 14. Biological Importance of Triazoles Triazolesa nd their derivatives are an interesting and important class of heterocyclic compoundst hat have been widely investigated and identified to hold great potential for various biological applications,including as antimicrobial, [65,66] analgesic, [67] anticonvulsant, [68] anti-inflammatory, [69] anticancer, [70][71] antihypertensive, [72] antimalarial, [73] anti-HIV, [74] hypoglycemic, [75] antidepressant, [76] antitubercular, [77,78] antioxidant, [79] antiviral, [80] anthelmintic, [81] anti-TNF (tumor necrosis factor), [82] antihistaminic, [83] antithyroid, [84] antiproliferative, [85] and antiasthmatic agents, [86] as well as in insecticides [87] and plant-growth regulators. [88] Owing to their structural similarities, triazoles have been used to mimic peptidea nd disulfide bonds, to link functional groupst ogethera nd for bioconjugationw ith various functional groups to increaset heir metabolic stabilitya nd peptidefunctions.…”