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

Abstract

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.

Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

“…The 110 assayed synthetic compounds (Table S1, Supplementary information), were prepared as described in our previous reports [19][20][21][22][23][24][25][26][27][28][29] . Reagents were obtained from Sigma-Aldrich Õ (St. Louis, MO) and solvents from Vetec (Duque de Caxias, RJ, Brazil).…”

A "green" synthesis of N-(quinoline-3-ylmethylene)benzohydrazide derivatives and their cytotoxicity activities

“…Some of the compounds synthesized showed significant cytotoxicity when tested against human lung adenocarcinoma cell line (A549) in vitro. Since quinoline 24 and benzohydrazide derivatives 25,26 have medicinal value, hence we believe that the present class of hydrazide derivatives represents an interesting profile for further experimental investigations especially in the area of anticancer research.…”

Drug Design for Chagas'Disease: Advances and Challenges

“…Ainda com relação ao composto 36, ensaios in vivo em modelo murino, comprovaram sua atividade e a DL 50 de 2 g/kg de peso. 69 Tais fatos respondem pelo caráter altamente promissor desse composto como candidato a fármaco.…”

“…99 Utilizando a base Chemdiv, com 700.000 compostos, a triagem virtual baseada em farmacóforos da cruzaína selecionou 20 compostos, 11 dos quais disponíveis comercialmente. 100 Ensaiados em cruzaína in vitro, alguns dos compostos apresentaram IC 50 102 Os resultados apontam para a relevância do perfil hidrofóbico à atividade biológica estudada.…”