Síntese de derivados N-aril-1-fenil-1H-pirazol-carboxamidas e híbridos 4-(metiltio)fenoxi-pirazol-imidazolina com potencial ação tripanocida

Abstract

Pyrazole is a five-membered nitrogenous heterocycle present in compounds with a broad spectrum of biological activity, such as anti-inflammatory and antiparasitic. Many studies have been published involving pyrazole derivatives with action against Trypanosoma cruzi (T. cruzi), the causative agent of Chagas Disease (CD) that mainly affects underdeveloped countries in Latin America and it is one of the 20 neglected tropical diseases (NTDs), according to the World Health Organization (WHO). Chemotherapy consists of benznidazole (Bz) and nifurtimox (NF), drugs that are not capable of curing the disease in the chronic phase and have several side effects. In this context, our research group has synthesized several pyrazole derivatives and tested them against the infecting forms of T. cruzi. The aim of this work was to synthesize and evaluate the trypanocidal action of 20 N-aryl-1-phenyl-1H-pyrazole-4-carboxamide derivatives 1(a-t) and 11 hybrids 4-(1-(2-(4-(methylthio)phenoxy)ethyl)-4,5-dihydro-1H-imidazol-2-yl)-1-phenyl-1H-pyrazole 2(a-k). In this work, 20 final products 1(a-t) were synthesized in 27-98% yield in 4 steps passing through the synthesis of the following intermediates: ethyl 1-phenyl-1H-pyrazole-4-carboxylate 4 (60% yield), 1-phenyl-1H-pyrazole-4-carboxylic acid 3 (90% yield). In addition, the compounds required for the synthesis of 2(a-k) were obtained: 1-aryl-1H-pyrazole-4-carbonitriles 8(a,e,f,i) in 76-98% yield, 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles 7(a,b,e-k) in 49-85% yield and 4-(methylsulfinyl)phenoxy-1-(2-bromoethane) in 38% yield. The latter replacing the initially planned analogous compound, 4-(methylthio)phenoxy-1-(2-dibromoethane) 6 . Several methodologies for obtaining product 2a were evaluated in order to optimize the synthesis to obtain the other products of series 2(b-k). However, after 13 attempts, the product was not obtained. Anti-T. cruzi activity and cytotoxicity tests involving 1(a-s) were performed. The best result was obtained for the N-(3,5-dichlorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide derivative 1d, whose IC50 values against the trypomastigote and amastigote forms of the protozoan were 9.54 ± 0.25 and 7.74 ± 2.21 μM, respectively. The products showed no toxicity to Vero cells, since all CC50 values were greater than 500 μM.