title: Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy-induced painful neuropathy.
abstract: 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.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Salvador, Bahia, Brazil.
authors.forename: Diogo Rodrigo Magalhaes
authors.initials: DRM
authors.lastname: Moreira
authors.affiliation: Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
authors.forename: Dourivaldo Silva
authors.initials: DS
authors.lastname: Santos
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Salvador, Bahia, Brazil.|Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
authors.forename: Renan Fernandes do
authors.initials: RFD
authors.lastname: Espírito Santo
authors.affiliation: Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
authors.forename: Flávia Evangelista Dos
authors.initials: FED
authors.lastname: Santos
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, Recife, PE, Brazil.
authors.forename: Gevanio Bezerra
authors.initials: GB
authors.lastname: de Oliveira Filho
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, Recife, PE, Brazil.
authors.forename: Ana Cristina Lima
authors.initials: ACL
authors.lastname: Leite
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Salvador, Bahia, Brazil.|Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, Bahia, Brazil.
authors.forename: Milena Botelho Pereira
authors.initials: MBP
authors.lastname: Soares
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Salvador, Bahia, Brazil.|Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
authors.forename: Cristiane Flora
authors.identifier: 0000-0002-0113-7864
authors.initials: CF
authors.lastname: Villarreal
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010146:Pain / Q000139:chemically induced* / Q000188:drug therapy*; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D053778:Thiazolidines / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D053778:Thiazolidines; D000077150:Oxaliplatin
keywords: PPAR; analgesic; glitazones; neuropathic pain; oxaliplatin