Influência de modificações estruturais no efeito antinociceptivo e anti inflamatório do 7-cloro-4-(fenilselanil) quinolina em camun

Abstract

Many studies have demonstrated that small structural changes are responsible for large modifications in the pharmacological activities of molecules. Our research group has been dedicated to the study of the pharmacological properties of 7-chloro-4-(phenylselenyl)quinoline (4-PSQ), which exerts antinociceptive and anti-inflammatory actions in different experimental models in mice. Therefore, in this study, we investigated the structure-activity relationship of 4-PSQ and its analogues 7-chloro-4-[(4-fluorophenyl)selenyl]quinoline (a), 7- chloro-4-{[3-(trifluoromethyl)phenyl]selenyl}quinoline (b), 4-((3,5- bis(trifluoromethyl)phenyl)selenyl)-7-chloroquinoline (c), 7-chloro-4-[(2,4,6- trimethyl)selenyl]quinoline (d), and 7-chloroquinoline-4-selenic acid (e) in models of acute inflammation, chemical, thermal, and mechanical nociception in mice. Additionally, the chemical structures of 4-PSQ and its analogues a (-F), b (-CF3), c (-Bis-CF3), d (-CH3) and e (-OOH) were subjected to an in silico process at in order to analyze their pharmacokinetic properties and bioactivities. The results of this study demonstrated that all compounds exerted antinociceptive effects in chemical and thermal nociception models, except compound d (-CH3) and compound e (-OOH) which did not show antinociceptive effects in the hot plate test, a thermal assay nociceptive, indicating no central effect. Furthermore, treatments with all compounds did not cause locomotor changes in mice. The in silico data regarding the pharmacokinetic properties of the compounds revealed that only compound c (Bis-CF3) showed low gastrointestinal absorption, and that both compounds c (Bis-CF3) and e (-OOH) do not have the ability to penetrate the barrier blood brain activity, indicating that compound e does not produce a central antinociceptive effect, as confirmed by the hot plate test. However, the results on the bioactivity of the compounds, regarding the potential of each molecule to interact in specific biological processes, were similar. In general, our data indicate that the insertion of substituents can alter the efficiency of 4-PSQ as an antinociceptive and anti-inflammatory agent. The data also showed that the insertion of -Bis-CF3, -F and -CH3 substituents in the 4-PSQ skeleton did not alter the duration of antinociceptive action in a model of acute inflammatory pain induced by complete Freund's adjuvant (CFA). Therefore, more studies are needed to expand our knowledge about these structure-activity relationships.