Despite therapeutic advances, inflammatory diseases such as diabetes remain associated with pain, oxidative stress, and adverse effects from conventional drugs. The involvement of the TRPA1 channel in inflammation and nociception is still poorly explored in metabolic disease models. In addition, there is a lack of studies evaluating alternative compounds, such as chalcones, capable of simultaneously targeting inflammation, pain, and hyperglycemia. Therefore, a significant gap exists regarding the use of chalcones as multifunctional therapeutic agents, particularly in experimental models such as zebrafish. This study reports the in vitro, in vivo and in silico results of the antinociceptive, anti-inflammatory and blood glucose-lowering effects of the synthetic chalcone ( E )-1-(2-hydroxyphenyl)-3-(thiophen-2-yl)prop-2-in-1-one (CHALTOF). Each animal (n=6/group) was treated intraperitoneally ( i.p .; 20 µL) with the synthetic chalcone (4, 20 and 40 mg/kg) and with the vehicle (DMSO 3%; 20 µL) and subjected to locomotor activity and acute toxicity at 96 hours, formalin-induced nociception and carrageenan-induced abdominal edema causing inflammation in adult zebrafish. Acute hyperglycemia was induced by sucrose (2.5 g/kg;) and chronic hyperglycemia by sucrose (83.25 mM/L) for 7 days. The groups of hyperglycemic animals (n = 6/group) received the following treatments: CHALTOF (40 mg/kg); - acarbose (300 mg/kg), metformin (200 mg/kg); 3% DMSO and naive. After 1 hour and 30 minutes(acute) and after 4 hours/11 days (chronic), blood glucose levels were measured with a glucometer. The ROS levels in the liver and brain of the hyperglycemic zebrafish were analyzed. CHALTOF caused antinociceptive and anti-inflammatory effects in zebrafish and also showed an inhibitory effect on NO production in J774A.1 cells compared to control groups. The in silico study suggests that these effects on pain and inflammation are related to the interaction of CHALTOF with TRPA1 and TRPV1 receptors. The molecular dynamics simulations revealed CHALTOF showed stable binding to TRPV1 (−104.5 kcal·mol⁻¹) and TRPA1 (−11.7 kcal·mol⁻¹), with slightly weaker affinity than capsaicin (−114.1 kcal·mol⁻¹) and canfor (−14.1 kcal·mol⁻¹). For CtMGAM, binding was much lower (−16.5 vs. −351.8 kcal·mol⁻¹ for acarbose), indicating weak inhibition. Overall, CHALTOF preferentially interacts with sensory receptors, showing potential as a selective modulator.
Barbosa et al. (Thu,) studied this question.