4-Phenyl-1,3-thiazole-2-amines as scaffolds for new antileishmanial agents.

Autor: Rodrigues CA; 1Chemical and Pharmaceutical Research Group, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil., Dos Santos PF; 1Chemical and Pharmaceutical Research Group, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil., da Costa MOL; 1Chemical and Pharmaceutical Research Group, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil., Pavani TFA; 1Chemical and Pharmaceutical Research Group, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil., Xander P; 2Laboratory of Cellular Immunology and Biochemistry of Fungi, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil., Geraldo MM; 2Laboratory of Cellular Immunology and Biochemistry of Fungi, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil., Mengarda A; 3Research Group of Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 88, Guarulhos, SP 07020-071 Brazil., de Moraes J; 3Research Group of Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 88, Guarulhos, SP 07020-071 Brazil., Rando DGG; 1Chemical and Pharmaceutical Research Group, Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Rua São Nicolau, 210, 2o andar, Diadema, SP 09913-030 Brazil.
Jazyk: angličtina
Zdroj: The journal of venomous animals and toxins including tropical diseases [J Venom Anim Toxins Incl Trop Dis] 2018 Sep 10; Vol. 24, pp. 26. Date of Electronic Publication: 2018 Sep 10 (Print Publication: 2018).
DOI: 10.1186/s40409-018-0163-x
Abstrakt: Background: There is still a need for new alternatives in pharmacological therapy for neglected diseases, as the drugs available show high toxicity and parenteral administration. That is the case for the treatment of leishmaniasis, particularly to the cutaneous clinical form of the disease. In this study, we present the synthesis and biological screening of eight 4-phenyl-1,3-thiazol-2-amines assayed against Leishmania amazonensis . Herein we propose that these compounds are good starting points for the search of new antileishmanial drugs by demonstrating some of the structural aspects which could interfere with the observed activity, as well as suggesting potential macromolecular targets.
Methods: The compounds were easily synthesized by the methodology of Hantzsch and Weber, had their purities determined by Gas Chromatography-Mass spectrometry and assayed against the promastigote forms of Leishmania amazonensis as well as against two white cell lines (L929 and THP-1) and the monkey's kidney Vero cells. PrestoBlue® and MTT viability assays were the methodologies applied to measure the antileishmanial and cytotoxic activities, respectively. A molecular modeling target fishing study was performed aiming to propose potential macromolecular targets which could explain the observed biological behavior.
Results: Four out of the eight compounds tested exhibited important anti-promastigote activity associated with good selectivity indexes when considering Vero cells. For the most promising compound, compound 6 , IC 50 against promastigotes was 20.78 while SI was 5.69. Compounds 3 (IC 50 : 46.63 μM; SI: 26.11) and 4 (IC 50 : 53.12 μM; SI: 4.80) also presented important biological behavior. A target fishing study suggested that S-methyl-5-thioadenosine phosphorylase is a potential target to these compounds, which could be explored to enhance activity and decrease the potential toxic side effects.
Conclusions: This study shows that 4-phenyl-1,3-thiazol-2-amines could be good scaffolds to the development of new antileishmanial agents. The S-methyl-5-thioadenosine phosphorylase could be one of the macromolecular targets involved in the action.
Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Databáze: MEDLINE
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