Estudos in silico, in vitro e in vivo na investigação da atividade antiasmática de cumarinas e derivados

Abstract

Asthma is characterized as a heterogeneous disease marked by chronic inflammation, bronchial hyperresponsiveness, and airway remodeling. In this context, natural compounds have attracted increasing scientific interest, with coumarins and their derivatives standing out as potential therapeutic agents. Thus, the main objective of this thesis was to use in silico, in vitro, and in vivo methods to investigate coumarins and their derivatives in order to identify compounds with greater antiasthmatic potential. In the systematic review, articles published in the last ten years (2014–2024) were analyzed, selected according to PRISMA guidelines from the PubMed, Virtual Health Library (BVS), and ScienceDirect databases. After applying the inclusion criteria, eighteen studies were selected. Among the most investigated molecules were imperatorin and osthole, which demonstrated the ability to promote relaxation of airway smooth muscle, reduce inflammatory processes, and decrease the release of Th2 cytokines (IL-4, IL-5, and IL-13), in addition to favoring immune mechanisms associated with Th1 cells, macrophages, and dendritic cells. Of this context, QSAR models were developed from 21 coumarin analogs described in the literature with tracheal relaxant activity, using different modeling strategies and molecular descriptor selection. Based on these models, five designed and commercially available coumarins were evaluated in silico, presenting predicted activities within a satisfactory range for future experimental validation. In parallel, 7- hydroxycoumarin (HXC), present in the laboratory compound library, was subjected to in vivo assays to evaluate its expectorant and antitussive potential. HXC demonstrated a robust antitussive effect in animal models, without associated expectorant activity and without signs of toxicity up to a dose of 300 mg/kg, being active at doses of 10, 30, and 100 mg/kg. The observed mechanism indicated that the antitussive effect depends on the integrity of the opioid system, being antagonized by naloxone. However, molecular docking studies did not show relevant direct interaction between HXC and opioid receptors, suggesting an indirect mechanism in the modulation of the cough reflex. Taken together, the results indicate that although they belong to the same chemical class, coumarins may present distinct and complementary pharmacological profiles in the pathophysiology of asthma.