Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy‐induced painful neuropathy

• Published in: Chemical biology & drug design Vol. 90; no. 2; pp. 297 - 307
• Main Authors: Moreira, Diogo Rodrigo Magalhaes, Santos, Dourivaldo Silva, Espírito Santo, Renan Fernandes do, Santos, Flávia Evangelista dos, Oliveira Filho, Gevanio Bezerra, Leite, Ana Cristina Lima, Soares, Milena Botelho Pereira, Villarreal, Cristiane Flora
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.08.2017
• Subjects: analgesic; Analgesics - chemistry; Analgesics - therapeutic use; Animals; Antineoplastic Agents - adverse effects; Biochemistry & Molecular Biology; Chemistry, Medicinal; glitazones; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Neoplasms - drug therapy; Neuralgia - chemically induced; Neuralgia - drug therapy; neuropathic pain; Organoplatinum Compounds - adverse effects; oxaliplatin; Pain - chemically induced; Pain - drug therapy; Pain Measurement; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - drug therapy; Pharmacology & Pharmacy; PPAR; Science & Technology; Thiazolidines - chemistry; Thiazolidines - therapeutic use; OXIDATIVE STRESS; analgesic; DRUG DISCOVERY; TACTILE ALLODYNIA; AGONISTS; PACLITAXEL; neuropathic pain; PPAR; INFLAMMATION; ACTIVATED-RECEPTOR-GAMMA; oxaliplatin; MICE; glitazones
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12951

Chemotherapy‐induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy‐induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potential analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond. The analgesic potential of the compounds was investigated in a mice model of oxaliplatin‐induced neuropathic pain, using von Frey, rota‐rod and open‐field tests. Except for compound 14, these thiazolidinones exhibited antinociceptive property without causing motor impairment. Thiazolidinones 12, 15 and 16 displayed a dose‐dependent antinociceptive effect, with similar efficacy and enhanced potency than gabapentin, the gold standard drug used for neuropathic pain. In addition, the antinociceptive activity of 16 lasted longer than gabapentin. The antinociceptive effect of thiazolidinones was prevented by GW9662, a PPARγ antagonist. The main antinociceptive compounds exhibited positive Lipinski's index, predicting their oral bioavailability. In conclusion, the structural design performed here led to the identification of new compounds endowed with potent antinociceptive activity, potentially useful to treat chemotherapy‐induced neuropathic pain. Chemotherapy‐induced neuropathy is a refractory pain condition resulting from chemotherapy for cancers. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of thiazolidinones with antinociceptive effects in a mice model of oxaliplatin‐induced neuropathic pain. Thiazolidinones displayed dose‐dependent and potent antinociceptive effects, possibly mediated by agonistic properties in PPAR. The structural design of thiazolidinones is an efficient strategy to optimize its pharmacological properties, aiming the control of the refractory neuropathic pain.