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Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative.

Abstract The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50 = 259.4 ± 6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50 = 188.2 ± 47.5 μM), with no harmful effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50 of about 191.8 ± 10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50 of 255.1 ± 3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi, offering new insights into CD treatment suggesting additional in vivo tests.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title biomed research international
Publication Year Start




PMID- 28316976
OWN - NLM
STAT- MEDLINE
DA  - 20170320
DCOM- 20170417
LR  - 20170417
IS  - 2314-6141 (Electronic)
VI  - 2017
DP  - 2017
TI  - Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a
      Phenyl-t-Butylnitrone Derivative.
PG  - 2483652
LID - 10.1155/2017/2483652 [doi]
AB  - The therapeutic options for Chagas disease are limited and its treatment presents
      a number of drawbacks including toxicity, drug resistance, and insufficient
      effectiveness against the chronic stage of the disease. Therefore, new
      therapeutical options are mandatory. In the present work, we evaluated the effect
      of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi 
      forms. LQB 123 presented a trypanocidal effect against bloodstream
      trypomastigotes (IC50 = 259.4 +/- 6.1 muM) and intracellular amastigotes
      infecting peritoneal macrophages (IC50 = 188.2 +/- 47.5 muM), with no harmful
      effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a 
      high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes
      submitted to LQB 123 presented an IC50 of about 191.8 +/- 10.5 muM and
      epimastigotes forms incubated with different concentrations of LQB 123 presented 
      an inhibition of parasite growth with an IC50 of 255.1 +/- 3.6 muM. Finally, we
      investigated the mutagenic potential of the nitrone by the Salmonella/microsome
      assay and observed no induction of mutagenicity even in concentrations as high as
      33000 muM. Taken together, these results present a nonmutagenic compound, with
      trypanocidal activity against all relevant forms of T. cruzi, offering new
      insights into CD treatment suggesting additional in vivo tests.
FAU - Cupello, Mauricio Peixoto
AU  - Cupello MP
AD  - Laboratorio de Interacao Tripanossomatideos e Vetores, Departamento de
      Bioquimica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Unidade de Desenvolvimento
      Tecnologico (UDT) de Triagem de Compostos Quimicos para Doencas Negligenciadas
      com Enfase Farmacologica contra a Doenca de Chagas, Universidade do Estado do Rio
      de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Saraiva, Francis Monique
AU  - Saraiva FM
AD  - Laboratorio de Interacao Tripanossomatideos e Vetores, Departamento de
      Bioquimica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Unidade de Desenvolvimento
      Tecnologico (UDT) de Triagem de Compostos Quimicos para Doencas Negligenciadas
      com Enfase Farmacologica contra a Doenca de Chagas, Universidade do Estado do Rio
      de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Ippolito, Pedro
AU  - Ippolito P
AD  - Laboratorio de Interacao Tripanossomatideos e Vetores, Departamento de
      Bioquimica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Fernandes, Andreia da Silva
AU  - Fernandes AD
AD  - Laboratorio de Mutagenese Ambiental LABMUT, Departamento de Biofisica e
      Biometria, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado 
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Menna-Barreto, Rubem Figueiredo Sadoko
AU  - Menna-Barreto RF
AUID- ORCID: 0000-0002-1352-0641
AD  - Laboratorio de Biologia Celular, IOC-FIOCRUZ, Rio de Janeiro, RJ, Brazil.
FAU - Costa, Debora de Sousa Dos Santos
AU  - Costa DS
AD  - Departamento de Quimica Organica, Universidade do Estado do Rio de Janeiro, Rio
      de Janeiro, RJ, Brazil.
FAU - Paula, Jessica Isis Oliveira
AU  - Paula JI
AD  - Laboratorio de Interacao Tripanossomatideos e Vetores, Departamento de
      Bioquimica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Unidade de Desenvolvimento
      Tecnologico (UDT) de Triagem de Compostos Quimicos para Doencas Negligenciadas
      com Enfase Farmacologica contra a Doenca de Chagas, Universidade do Estado do Rio
      de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Costa, Paulo Roberto Ribeiro
AU  - Costa PR
AD  - Laboratorio de Quimica Bioorganica, NPPN, Universidade Federal do Rio de Janeiro,
      Rio de Janeiro, RJ, Brazil.
FAU - Nogueira, Natalia Pereira
AU  - Nogueira NP
AUID- ORCID: 0000-0003-3258-607X
AD  - Laboratorio de Interacao Tripanossomatideos e Vetores, Departamento de
      Bioquimica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Unidade de Desenvolvimento
      Tecnologico (UDT) de Triagem de Compostos Quimicos para Doencas Negligenciadas
      com Enfase Farmacologica contra a Doenca de Chagas, Universidade do Estado do Rio
      de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Felzenswalb, Israel
AU  - Felzenswalb I
AUID- ORCID: 0000-0003-1677-197X
AD  - Laboratorio de Mutagenese Ambiental LABMUT, Departamento de Biofisica e
      Biometria, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado 
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
FAU - Dias, Ayres Guimaraes
AU  - Dias AG
AD  - Departamento de Quimica Organica, Universidade do Estado do Rio de Janeiro, Rio
      de Janeiro, RJ, Brazil.
FAU - Paes, Marcia Cristina
AU  - Paes MC
AUID- ORCID: 0000-0003-2247-8251
AD  - Laboratorio de Interacao Tripanossomatideos e Vetores, Departamento de
      Bioquimica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado
      do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Unidade de Desenvolvimento
      Tecnologico (UDT) de Triagem de Compostos Quimicos para Doencas Negligenciadas
      com Enfase Farmacologica contra a Doenca de Chagas, Universidade do Estado do Rio
      de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciencia e
      Tecnologia, Entomologia Molecular (INCT-EM), Rio de Janeiro, RJ, Brazil.
LA  - eng
PT  - Journal Article
DEP - 20170215
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
RN  - 0 (Cyclic N-Oxides)
RN  - 0 (Mutagens)
RN  - 0 (Nitrogen Oxides)
RN  - 0 (Trypanocidal Agents)
RN  - 0 (nitrones)
RN  - 3I91332OPG (phenyl-N-tert-butylnitrone)
SB  - IM
MH  - Animals
MH  - Chagas Disease/*drug therapy
MH  - Cyclic N-Oxides/*chemistry
MH  - Drug Evaluation, Preclinical
MH  - Inhibitory Concentration 50
MH  - Macrophages, Peritoneal/drug effects/parasitology
MH  - Mice
MH  - Mutagenesis
MH  - Mutagens/*chemistry
MH  - Nitrogen Oxides/chemistry
MH  - Salmonella
MH  - Trypanocidal Agents/chemistry/*pharmacology
MH  - Trypanosoma cruzi/*drug effects
PMC - PMC5339480
COI - The authors report no conflict of interests in this work.
EDAT- 2017/03/21 06:00
MHDA- 2017/04/18 06:00
CRDT- 2017/03/21 06:00
PHST- 2016/09/10 [received]
PHST- 2017/01/04 [accepted]
AID - 10.1155/2017/2483652 [doi]
PST - ppublish
SO  - Biomed Res Int. 2017;2017:2483652. doi: 10.1155/2017/2483652. Epub 2017 Feb 15.

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