Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: Discovery of novel N-arylideneamino quinazolin-4(3 H)-one compounds derived from natural safrole

We describe herein the discovery of novel quinazolin-4-one derivatives LASSBio-1240 ( 3b) and LASSBio-1272 ( 3d), as conformationally constrained N-acylhydrazone derivatives, which present remarkable in vivo antinociceptive profile. 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(3 H)-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.