RESUMO
This work evaluates the antinociceptive properties of benzofuranones using chemically induced models of pain and the hot plate test. All the compounds exhibited significant antinociceptive activity, with 3-[2-(4-chlorophenyl)-2-oxoetil]-2-benzofuran-1(3H)-one (3d) being the most active. According to the application of the Topliss method, the 2π-π(2) parameter was the preponderant one, indicating that the hydrophobicity (π) seems to be more involved in the antinociceptive activity. Based on the table of other possible substituents proposed by Topliss, three derived from compound 3d were tested. 3-[2-(3-methoxyphenyl)-2-oxoetil]-2-benzofuran-1(3H)-one (3g) showed greater antinociceptive activity with better pharmacokinetic properties predicted. These results show the efficiency of the Topliss Method as a research tool for the discovery of potential candidate molecules for a new antinociceptive drug.
Assuntos
Analgésicos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Benzofuranos/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/síntese química , Analgésicos/química , Animais , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Dor/induzido quimicamente , Medição da Dor , Relação Estrutura-AtividadeRESUMO
Chalcones represent an important group of natural or synthetic compounds with a variety of biological activities including antinociceptive and anti-inflammatory ones. The aim of this work was the synthesis of a new benzofuranone compound and evaluation of its antinociceptive potential in mice. The new benzofuranone 4 was synthesized from chalcone 3. The antinociceptive activity of 4 was determined by writhing, formalin, capsaicin, and glutamate and hot-plate tests. Compound 4 caused potent and dose-related inhibition against the writhing test with ID50 6.1 (5.1-7.6) µmol/kg, i.p., being about 15 times more active than the reference drugs, acetyl salicylic acid and acetaminophen. It was also effective in a dose-dependent manner in significantly reducing the painful stimulus in both phases of formalin, in the capsaicin and in the glutamate test with ID50 values of 27.3 (24.5-30.6) and 18.9 (18.5-19.4) µmol/kg (first and second phase), 12.6 (9.8-16.2) and 24.5 (20.4-29.6) µmol/kg respectively. The results showed that the studied compound exhibits both central and peripheral antinociceptive activities and might be further used as a model to obtain new and more potent analgesic drugs.
Assuntos
Analgésicos/farmacologia , Benzofuranos/farmacologia , Chalcona/farmacologia , Acetaminofen/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Aspirina/farmacologia , Benzofuranos/síntese química , Capsaicina/metabolismo , Chalcona/síntese química , Relação Dose-Resposta a Droga , Formaldeído/metabolismo , Ácido Glutâmico/metabolismo , Modelos Lineares , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Medição da DorRESUMO
Nine acetamidochalcones were synthesized and evaluated as antinociceptive agents using the mice writhing test. Given intraperitoneally all the compounds were more effective than the two reference analgesic drugs (acetylsalicylic acid and acetaminophen) used for comparison. N-{4-[(2E)-3-(4-nitrophenyl)prop-2-enoyl]phenyl}acetamide (6) was the most effective compound and was therefore selected for more detailed studies. It caused dose-related inhibition in the writhing test, being about 32 to 34-fold more potent than the standard drugs. It was also effective in the second phase of the formalin test and the capsaicin test. These acetamidochalcones, especially compound 6, might be further used as models to obtain new and more potent analgesic drugs.
