title: Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
abstract: We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Uruguay.
authors.forename: Paola
authors.initials: P
authors.lastname: Hernández
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cabrera
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Laura
authors.initials: L
authors.lastname: Celano
authors.forename: Inés
authors.initials: I
authors.lastname: Tiscornia
authors.forename: Thiago
authors.initials: T
authors.lastname: Rodrigues da Costa
authors.forename: Leonor
authors.initials: L
authors.lastname: Thomson
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollati-Fogolín
authors.forename: Ana Luisa P
authors.initials: AL
authors.lastname: Miranda
authors.forename: Lidia M
authors.initials: LM
authors.lastname: Lima
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000276:immunology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy; D051381:Rats
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D006835:Hydrazones; D016209:Interleukin-8; D016859:Lipoxygenase Inhibitors; D010069:Oxadiazoles; C010166:furoxans