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

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, IC50 against promastigotes was 20.78 while SI was 5.69. Compounds 3 (IC50: 46.63 µM; SI: 26.11) and 4 (IC50: 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.

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

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, IC50 against promastigotes was 20.78 while SI was 5.69. Compounds 3 (IC50: 46.63 µM; SI: 26.11) and 4 (IC50: 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.(AU)

Evaluation of Experimental Infection with L. ( L.) Amazonensis in X-Linked Immunodeficient Mice.

B-1 cells are a subtype of B cells with peculiar characteristics. These cells are distinct from B-2 lymphocytes in their morphology, ontogeny, tissue distribution, and phenotypic functional features. B-1 cells can participate in the immune response in several ways, for example, by being recruited to inflammatory foci, producing large amounts of IL-10 cytokine, and differentiating into IgM-secreting cells or phagocytes. Nevertheless, the role of B-1 cells in the pathogenesis of experimental leishmaniasis has not been fully elucidated. Here we evaluated the role of B-1 cells in Leishmania ( L.) amazonensis infection using X-linked immunodeficient (XID) mice that possess a mutation in Bruton's tyrosine kinase (Btk) that leads to a reduced number of B-1 cells. The course of infection and the corresponding immune response were analyzed in infected mice. XID mice showed an increase in parasite number in paws, lymph nodes, and spleen compared to BALB/c infected controls. Infected XID mice had higher IL-10 levels and lower anti- Leishmania IgM. The adoptive transfer of peritoneal B-1 cells into XID mice restored peritoneal B-1 cells and parasite burden in the footpad in a pattern similar to that observed in the BALB/c controls at 10 wk. Our results demonstrate the higher susceptibility of XID mice to infection with L. ( L.) amazonensis compared to controls. In addition, we show that the presence of B-1 cells contributes to improved animal resistance to parasites, suggesting that these cells are involved in the control of cutaneous infection caused by L. ( L.) amazonensis.