Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole.
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.
Maia
Rodolfo C
RC
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.
Silva
Leandro L
LL
Mazzeu
Eduardo F
EF
Fumian
Milla M
MM
de Rezende
Claudia M
CM
Doriguetto
Antonio C
AC
Corrêa
Rodrigo S
RS
Miranda
Ana Luisa P
AL
Barreiro
Eliezer J
EJ
Fraga
Carlos Alberto Manssour
CA
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*
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; D012451:Safrole