title: Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole.
abstract: In this work we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and platelet anti-aggregating properties of new 3-(arylideneamino)-2-methyl-6,7-methylenedioxy-quinazolin-4(3H)-one derivatives (3a-j), designed as conformationally constrained analogues of analgesic 1,3-benzodioxolyl-N-acylhydrazones (1) previously developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (2) as starting material. The pharmacological assays lead us to identify compounds LASSBio-1240 (3b) and LASSBio-1272 (3d) as new analgesic prototypes, presenting an antinociceptive profile more potent and effective than dipyrone and indomethacin used, respectively, as standards in AcOH-induced abdominal constrictions assay and in the formalin test. These results confirmed the success in the exploitation of conformation restriction strategy for identification of novel cyclic N-acylhydrazone analogues with optimized analgesic profile.
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68023, ZIP 21941902 Rio de Janeiro, RJ, Brazil.
authors.forename: Rodolfo C
authors.initials: RC
authors.lastname: Maia
authors.forename: Leandro L
authors.initials: LL
authors.lastname: Silva
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Mazzeu
authors.forename: Milla M
authors.initials: MM
authors.lastname: Fumian
authors.forename: Claudia M
authors.initials: CM
authors.lastname: de Rezende
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Doriguetto
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Corrêa
authors.forename: Ana Luisa P
authors.initials: AL
authors.lastname: Miranda
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Carlos Alberto Manssour
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012451:Safrole / Q000737:chemistry*
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; D012451:Safrole