1533-22-8Relevant academic research and scientific papers
New approach towards the synthesis of selenosemicarbazones, useful compounds for Chagas' disease
Pizzo, Chiara,Faral-Tello, Paula,Yaluff, Gloria,Serna, Elva,Torres, Susana,Vera, Ninfa,Saiz, Cecilia,Robello, Carlos,Mahler, Graciela
, p. 107 - 113 (2016/01/15)
Herein, we describe a new approach towards the synthesis of selenosemicarbazones. The reaction involves an O-Se exchange of semicarbazones using Ishihara reagent. Eleven selenosemicarbazones were prepared using this methodology, with low to moderate yields. Among the prepared compounds the m-bromo phenyl methyl derivative 1b was selected to be evaluated in vivo, in a murine model of acute Chagas' disease. Compound 1b 10 mg/kg bw/day reduced 50% of parasitaemia profile compared with the control group, but was less effective than Benznidazole (50 mg/kg bw/day reduced 90%) and toxic. These studies are important to guide future Chagas drug design.
Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Du, Xiaohui,Guo, Chun,Hansell, Elizabeth,Doyle, Patricia S.,Caffrey, Conor R.,Holler, Tod P.,McKerrow, James H.,Cohen, Fred E.
, p. 2695 - 2707 (2007/10/03)
American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be trypanocidal. We initially discovered that 3′-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3′-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC50 values in the low nanomolar range were identified. Eight additional analogues were trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.
