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.

Isomerization of Allylbenzenes

“…It should be noted here that research groups from Brazil have been very effective in using safrole 6 as starting material for the synthesis of various bioactive molecules . In these cases, the potassium hydroxide–alcohol solvent combination was used to isomerize the safrole allyl functional group, followed by subsequent multistep synthetic procedures to afford molecules with antihypertensive, antiplatelet, − vasodilatory, analgesic, ,, antipyretic, anti-inflammatory, ,, inotropism-increasing, and antithrombotic activities. For related studies on base-mediated (KOH or NaOH) isomerizations of safrole and related compounds, see refs , , and .…”

N-Substituted indole carbohydrazide derivatives: synthesis and evaluation of their antiplatelet aggregation activity

“…Furthermore, the N -acylhydrazone (NAH) moiety, have shown a series of biological activities such as analgesic, anti-inflammatory [13-20], protozoa proteases inhibition [21], HIV-1 reverse transcriptase dimmer destabilization [22], antibiotic and antifungal activities [23], and cardiovascular actions [24-28]. …”

Drug repurposing for Chagas disease: In vitro assessment of nimesulide against Trypanosoma cruzi and insights on its mechanisms of action

“…The chemoselective reduction of the nitro group of nimesulide. As shown in Fig 1B, to evaluate the role of nitroaromatic moiety of nimesulide structure, the aniline (4) prepared from nimesulide was obtained as described by Maia et al [22], using metallic iron in presence of aqueous ammonium chloride and ethanol reagent. The aniline (4) (199 mg; 65% yield) was obtained as a white crystalline solid [21,23].…”