Biochemical evaluation of a series of synthetic chalcone and hydrazide derivatives as novel inhibitors of cruzain from Trypanosoma cruzi

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 (IC50 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.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 IC50 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.CNPqFAPESPCAPE

Synthesis, screening for antiacetylcholinesterase activity and binding mode prediction of a new series of [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters

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 ¹H, 13C, 31P, and 19F 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.Uma nova série de nove 3-fosfato-(4,4,4-trifluor-butil)-carbamatos de etila (compostos fosfato-carbamato), foram obtidos através da reação de (4,4,4-trifluor-3-hidroxibut-1-il)-etil carbamatos com oxicloreto de fósforo seguido de adição de álcoois. Os produtos foram caracterizados por espectroscopia de RMN de ¹H, 13C, 31P e 19F, 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.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPES

Convergent synthesis and cruzain inhibitory activity of novel 2-(N `-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines

To search for new cruzain inhibitors, the synthesis of a series of novel 2-(N`-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines in a convergent manner is presented. The cruzain inhibitory activity of some of these compounds was evaluated and a binding model was proposed. All derivatives tested were active and the most significant inhibitory effect (80% at 100 mu M) and IC(50) value (85 mu M) were obtained from the 2-(N`-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine. Although further structural optimization to improve solubility is necessary, the molecular docking studies suggest that these inhibitors occupy the S2 pocket without irreversible enzyme inactivation, through hydrophobic interactions, thus, indicating a desirable mode of interaction for the design of novel inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)[477682/01-4]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP (Fundacao de Amparo a Pesquisa de Estado de Sao Paulo)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPES