Guanilidrazonas e tiossemicarbazonas como potenciais fármacos antiobesidade: estudos cinéticos e docking molecular frente à lipase de Candida rugosa

Abstract

Obesity is associated with the risk of type 2 diabetes, hypertension, coronary, cerebrovascular diseases, osteoarthritis, sleep apnea and certain types of cancer, in addition to the risk of developing depression, infertility, pregnancy problems and anomaly of reproductive hormones. Currently, the low prices of fatty foods and sugar consumption, contributes to the growth of the obesity rate, sometimes associated with sedentary lifestyle. The World Health Organization (WHO) reported that in 2016, more than 1.9 billion adults were overweight; among these, 650 million were obese. Pancreatic lipase (LP) is an enzyme of fundamental importance for hydrolysis of triacylglycerides and is responsible for the hydrolysis of 50 to 70% of the fat present in food. Orlistat is one of the few anti-obesity drugs that reduces fat absorption up to 30% by inhibiting pancreatic and gastric lipase, blocking the hydrolysis of triacylglycerols and subsequent excretion of fat. In point of view of the adverse effects and the absence of anti- obesity drugs, this thesis search to develop new lipase inhibitors prototypes based on the structural framework of guanylhydrazones (AGH) and thiosemicarbazones (TSC). Among the 22 biologically evaluated AGH compounds, the highest antilipase activity was (E)-2-(3,4- dicolorobenzylidene)hydrazine-1-carboximide with an IC50 of 11.16μM and kinetic behavior of competitive inhibition. However, a total of 144 compounds were evaluated using the virtual screening technique, among them, the unprecedented planned structure (9E,12E)-N-((2-((E)- 3,4-dichlorobenzylidene) hydrazine)(imino)methyl)octadeca-9,12-dienamide, with a fit score of 73.59, the molecular docking analysis showed only hydrophobic interactions in the substrate binding site, suggesting a kinetic behavior of competitive inhibition. Finally, this work presents a new possibility of developing prototypes with a pharmacologically accepted framework, proposing novel structures, contributing to the search for a effective, selective and safe candidate in the treatment of obesity.