Milena Botelho Pereira Soares, Diogo Rodrigo Magalhaes Moreira, Cristiane Flora Villarreal, Gevanio Bezerra Oliveira Filho, Flávia Evangelista dos Santos, Ana Cristina Lima Leite, Dourivaldo Silva Santos, Renan Fernandes do Espírito Santo
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.
