title: Docking, synthesis and anti-diabetic activity of novel sulfonylhydrazone derivatives designed as PPAR-gamma agonists.
abstract: Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats.
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. gsudo@icb.ufrj.br
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Lima
authors.forename: Sharlene L
authors.initials: SL
authors.lastname: Pereira
authors.forename: Margarete M
authors.initials: MM
authors.lastname: Trachez
authors.forename: Filipe P
authors.initials: FP
authors.lastname: da Costa
authors.forename: Beatriz J
authors.initials: BJ
authors.lastname: Souza
authors.forename: Carlos E S
authors.initials: CE
authors.lastname: Monteiro
authors.forename: Nelilma C
authors.initials: NC
authors.lastname: Romeiro
authors.forename: Éverton D
authors.initials: ÉD
authors.lastname: D'Andrea
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Sudo
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists*; D013311:Streptozocin; D013816:Thermodynamics
chemical_list: D006835:Hydrazones; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D013311:Streptozocin