Síntese e bioatividade de sistemas pirazolil-piridínicos poli-heterocíclicos trialometil substituídos

Abstract

This thesis describes the studies carried out using the reagent 6- hydrazinonicotinic hydrazide for the synthesis of new trihalomethylated pyrazolylpyridine systems using the 4-alkoxy-4-alkyl(aryl/heteroaryl-1,1,1-trihaloalk-3-en-2- ones [CX3C(O)CH=CROCH3, in which R = CH3, C6H5, 4-CH3C6H4, 4-OCH3C6H4, 2- Furyl and X = F, Cl]. In four reactional steps, compounds 6-[3-alkyl(aryl)-5-trifluoromethyl-1Hpyrazol- 1-yl]nicotinohydrazides were isolated after the treatment of their respective methyl nicotinate hydrochlorides with hydrazine hydrate. Because of the synthetic potential of these molecules, afterwards, type [3 + 2] and type [4 + 1] cyclocondensation reactions were carried out to develop various polyheterocyclic systems. Initially, systems containing trihalomethylated bis-pyrazolyl-pyridine were sythesized in yields of 67 91% and in a following step, are subjected to intramolecular dehydration reactions in the midst pyridine/benzene and thionyl chloride. Furthermore, this study shows the synthetic routes of systems 5-alkyl(aryl)-1,3,4-oxadiazolylpyrazolyl- pyridinic, 2-thione-3H-1,3,4-oxadiazolyl-pyrazolyl-pyridinic. Subsequently, to illustrate the possibility of obtaining different heterocycles, we describe an example of the convertion of 1,3,4-oxadiazole-2(3H)-thione into 2H-1,2,4- triazole-3(4H)-thione. Still, we describe the synthesis of 6-(2-thione-3H-1,3,4- oxadiazole-5-yl)-3(4H)-thioxo-2H-1,2,4-triazolo[4,3-a]pyridine, when reagent 6- hydrazinonicotinic hydrazide reacts with carbon disulfide under basic conditions. In continuation of the study, we demonstrate the synthesis of N-(2,5-dimethyl- 1H-pirrole-1-yl)-6-[3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazole-1- yl]nicotineamides, obtained when pyrazolyl-nicotinohydrazides reacts with hexane-2,5- dione. Finally, cyclocondensation reactions using aryl-aldehydes or 1-feniletanone in compounds 6-[3-alkyl(aryl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinohydrazides are described. In the second part of this study, the synthesized compounds were evaluated in vitro for antimicrobial activites by determining the minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) through broth microdilution against Gram-positive and Gram-negative bacteria and fungi of clinical interest; for their inhibitory activity of the acetylcholinesterase enzyme (AChE); for the antioxidant potential by the method of free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the total antioxidant capacity (TAC) of compounds was evaluated by the phosphomolybdenum assay. The compounds were characterized by 1H , 13C {1H}, 19F, COSY 90, DEPT 135, HSQC RMN Spectroscopy, Gas Chromatography coupled to Mass Spectrometry (GCMS), Liquid Chromatography coupled to Mass Spectrometry (LC-ESI-MS/MS), Infrared Spectroscopy (IR), X-Ray Diffraction and their purities determined by CHN Elemental Analysis.