A doença de Chagas, uma infecção parasitária amplamente distribuída na América Latina, é um problema grave de saúde pública com conseqüências devastadoras em termos de morbidade e mortalidade humana. A enzima cruzaína é a principal cisteíno protease do Trypanosoma cruzi, agente etiológico da tripanossomíase Americana ou doença de Chagas, e foi selecionada como alvo atrativo para o desenvolvimento de novos fármacos tripanocidas. No presente trabalho, a síntese e os efeitos inibitórios de uma série de trinta e três chalconas e sete hidrazidas são descritos contra a enzima cruzaína de T.cruzi. A maioria dos compostos mostraram inibição promissora in vitro (valores de IC 50 na faixa de 20-60 μM), o que sugere o potencial desses compostos como candidatos a líderes para contínuo desenvolvimento. Doze compostos são inéditos, sendo que quatro destes (7, 13, 16 e 18) estão entre os inibidores mais potentes da série.Chagas' disease, a parasitic infection widely distributed throughout Latin America, is a major public health problem with devastating consequences in terms of human morbidity and mortality. The enzyme cruzain is the major cysteine protease from Trypanosoma cruzi, the etiologic agent of American trypanosomiasis or Chagas' disease, and has been selected as an attractive target for the development of novel trypanocidal drugs. In the present work, we describe the synthesis and inhibitory effects of a series of thirty-three chalcone and seven hydrazide derivatives against the enzyme cruzain from T. cruzi. Most of the compounds showed promising in vitro inhibition (IC 50 values in the range of 20-60 μM), which suggest the potential of these compounds as lead candidates for further development. Twelve compounds have not been reported before, and four of them (7, 13, 16 e 18) are among the most potent inhibitors of the series.

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Este trabalho apresenta a síntese de duas novas séries de 6-trifluormetil-1,3-oxazinanas N-substituídas e 6-trifluormetil-1,3-oxazinan-2-onas N-substituídas, a partir da ciclização de 4-ilamino-1,1,1-trifluor-butan-2-óis com formaldeído e trifosgênio, respectivamente. Os 4-ilamino-1,1,1-trifluor-butan-2-óis foram obtidos através da reação de redução dos precursores 4-ilamino-1,1,1-trifluor-but-3-en-2-onas, utilizando hidrogênio e 10% Pd/C, com bons rendimentos.This work reports the synthesis of two new series of N-substituted 6-trifluoromethyl-1,3-oxazinanes and N-substituted 6-trifluoromethyl-1,3-oxazinan-2-ones from the cyclization of 4-ylamino-1,1,1-trifluoro-butan-2-ols with formaldehyde and triphosgene, respectively. The 4-ylamino-1,1,1-trifluoro-butan-2-ols were obtained in good yields from the reduction of the parent 4-ylamino-1,1,1-trifluoro-but-3-en-2-ones with hydrogen and 10% Pd/C. Keywords: γ-amino alcohols, β-enamino ketones, 1,3-oxazinanes, 1,3-oxazinan-2-ones, 1,3-oxazines Introduction 1,3-Oxazines belong to a class of compounds that have been largely studied due to their wide range of biological activities and easy synthetic accessibility. Special attention has been given to these compounds since the development of Efavirenz, a trifluoromethyl-1,3-oxazin-2-one, which is a non-nucleoside reverse transcriptase inhibitor that shows high activity against a variety of HIV-1 mutant strains. 1 Although, 1,3-oxazinanes have not been used as extensively as the parent 1,3-oxazines, probably due to the difficulties to synthesize the saturated 1,3-oxazine ring with a wide range of substituents, 1,3-oxazinanes exhibit a variety of biological activities. Just to mention a few, they are being explored as anti-inflammatory and agents for treating ulcers, allergies, asthma, arthritis, and diabetes. 2 1,3-Oxazinanes have been used as key intermediates in the synthesis of thrombolytic agents, 3 liquid crystal devices, 4 chiral auxiliaries in organic synthesis, 5,6 and 1,3-amino alcohols, 7-10 and β-carbolines. 11 The synthesis of 1,3-oxazinanes, is much less developed than the parent 1,3-oxazines and there are not many available synthesis for 1,3-oxazinanes described in the literature. One of the first methods reported to synthesize 5-nitro-5-alkyl-1,3-oxazinanes, from the reaction of a primary nitroalkane with formaldehyde and ammonia or primary amines, was explored in the fifties and sixties. 12 Another method to synthesize 1,3-oxazinanes is by peracid-induced ring opening of isoxazolidines derived from the reaction of nitrones and alkenes. 13 A chiral approach to the synthesis of 1,3-oxazinan-2-ones utilizes aspartic acid as the starting material in a multistep procedure that includes the formation of an epoxide containing a Cbz-protected arylamine as the key intermediate. The synthesis continues with the epoxide ring opening by sodium azide followed by an intramolecular cyclization of the hydroxy group with the benzylcarbamate group to give the desired 1,3-oxazinan-2-one. 14 1,3-Oxazinan-2-ones were also obtain...

adição de álcoois. Os produtos foram caracterizados por espectroscopia de RMN de 1 H, 13 C, 31 P e 19 F, CG-EM e análise elementar. Todos os compostos sintetizados foram testados para a inibição da enzima acetilcolinesterase (AChE) usando o método de Ellman. Todos os compostos analisados contendo os grupos carbamato e fosfato em sua estrutura, mostraram inibição enzimática, sendo que o composto contendo o grupo dietóxi (2b) apresentou a maior atividade inibitória. Estudos de modelagem molecular foram realizados para obter informações detalhadas entre o sítio ativo da enzima acetilcolinesterase e os compostos candidatos a inibição, obtendo-se valiosas informações estruturais com relação à inibição de enzima acetilcolinesterase.A series of nine new [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters (phosphate-carbamate compounds) was obtained through the reaction of (4,4,4-trifluoro-3-hydroxybut-1-yl)-carbamic acid ethyl esters with phosphorus oxychloride followed by the addition of alcohols. The products were characterized by 1 H, 13 C, 31 P, and 19 F NMR spectroscopy, GC-MS, and elemental analysis. All the synthesized compounds were screened for acetylcholinesterase (AChE) inhibitory activity using the Ellman method. All compounds containing phosphate and carbamate pharmacophores in their structures showed enzyme inhibition, being the compound bearing the diethoxy phosphate group (2b) the most active compound. Molecular modeling studies were performed to investigate the detailed interactions between AChE active site and small-molecule inhibitor candidates, providing valuable structural insights into AChE inhibition.