Avaliação da toxicidade e do efeito antidepressivo simile de um derivado chalcona (GA-4), por meio de metodologias in silico e in vivo

Abstract

Chalconas are an important chemical class in health by showing many interesting biological activities, in addition to a convenient synthesis. Different pharmacological activities are reported, which chalconas have, such as: anti-inflammatory, antimicrobial, antioxidant, cytotoxic, antitumor actions, among others. Therefore, this study aimed to investigate chalcone 3(benzo[d][1,3]dioxol-5-yl)-5-(thiophen-2yl)-4,5- dihydro-1H-pyrazole-1-carbothiamide, also known as GA-4, to evaluate its pharmacokinetics and in silicic toxicity, docking molecular as well as its toxicity in vivo. Subsequently, the acute toxicological study was performed in vivo, following the experimental protocols adopted at the Laboratory of Toxicological Tests (LABETOX) based on the Guide for Conducting Non-Clinical Studies and OECD 423 (2001). The acute in vivo toxicological study was subsequently performed, following the experimental protocols adopted at the Laboratory of Toxicological Trials (LABETOX) and the OECD 423 Guide (2001). Thus, a dose of 300 mg/kg of the test substance was administered in Wistar rats and subsequently no deaths was administered at a dose of 2000 mg/kg. After 14 days, the animals were euthanized for overdose of anesthetic, and his blood collected for evaluation of biochemical and hematological parameters. Histological analysis of the animals' organs was also performed. Mood disorder is a mental disorder, affecting about 300 million people worldwide, which can cause low self-esteem, sense of rejection, low energy, anhedonia, loss of appetite, insomnia, excessive concern, generating suffering and leading the patient to suicide. Subsequently psychopharmacological tests were performed in vivo, using Swiss mice: initially the open field test at doses of 50, 100 and 200 mg/kg, analyzing the parameters: Rearing, Grooming, Number of crosses, urinations and fecal cakes, and more specifically, to evaluate the antidepressant effect of the forced-birth test, the immobility time of the animals in the same doses of the open-field test was evaluated. As for its pharmacokinetics, the in silica studies show that it has a good theoretical oral absorption, with possible ability to cross the blood-brain barrier, and a low grade III acute theoretical toxicity, moreover it was observed that GA-04 bound to the same activation site of yohimbine, showing to be a possible antagonist of α2- adrenergic receptors. This was confirmed in the in vivo toxicity study, in which the substance GA-4 had a LD50 greater than 5000 mg/kg and was classified as low toxicity category 5 GSH. Twenty-one biochemical parameters were evaluated, with significant changes compared to control in only five dosages: total proteins, creatinine, sodium, calcium and lipase. As for the hematological parameters, there was no alteration in the erythrogram and plaquetogram, being detected an alteration only in the leukocytes. However, when performing the histological study of the animals' organs, no significant change was found when compared to the control group. Therefore, faced with such results, we can infer that the GA-4 is a potent candidate as a future antidepressant drug, since in addition to promising pharmacological results, it has a good theoretical oral absorption and low toxicity.