81529-61-5Relevant articles and documents
Schiff bases of 4-Phenyl-2-Aminothiazoles as hits to new antischistosomals: Synthesis, in vitro, in vivo and in silico studies
Amorim, Carina R.,Duque, Marcelo D.,Lopes, Andrey F. S.,Mengarda, Ana C. A.,Pavani, Thais F. A.,Rando, Daniela G. G.,Silva, Marcos P.,de Moraes, Josué
, (2020/05/18)
The treatment of schistosomiasis is based on a single drug, the praziquantel (PZQ), an oral bioavailable and efficient agent which causes minimal side effects. The main concern about this approach, however, is that relying on only one drug to treat a helminthic disease is a dangerous strategy since history shows that pathogens easily evolve to resistant forms. Actually, reports about experimental strains exhibiting low sensibility to PZQ can be found in literature. The search for new antischistosomals, consequently, is urgent. Here we report the synthesis of seventeen Schiff bases of 4-(4-Substituted phenyl)-N-(4-substituted benzylidene)thiazole-2-amines which were tested in vitro and in vivo against Schistosoma mansoni adult worms. Moreover, in silico studies to propose potential macromolecular targets and to predict the oral bioavailability were also performed. The analog GPQF-108 exhibited the best in vitro performance (IC50: 29.4 μM, SI:6.1) associated with promising in vivo activity, with a significant decrease in the adult life forms and oviposition. Oral bioavailability could be impaired by the predicted low water solubility of GPQF-108, although it also exhibited good membrane permeability. The water solubility, however, could be improved by decreasing the particles size. Serine/Threonine- and Tyrosine Kinases, Carbonic Anhydrase, Tyrosine Phosphatase and Arginase were predicted as potential macromolecular targets through which the GPQF-108 could be acting against the helminth. This class of compounds exhibited an interesting initial therapeutic profile with the advantage of being chemically diverse from the PZQ and be easily synthesized from commercial reagents which could lead to low-cost drugs. These aspects make this class of compounds interesting hits to be explored against schistosomiasis.
SUBSTITUTED AMINOTHIAZOLES AS INHIBITORS OF NUCLEASES
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Page/Page column 14-15; 40; 60, (2019/11/12)
The invention provides compounds represented by the structural formula (1): wherein R1, R2, R3, R4, R5, R6 are as defined in the claims. The compounds are inhibitors of nucleases, and are useful in particular in a method of treatment and/or prevention of proliferative diseases, neurodegenerative diseases, and other genomic instability associated diseases.
4-Phenyl-1,3-thiazole-2-amines as scaffolds for new antileishmanial agents
Rodrigues, Carina Agostinho,dos Santos, Paloma Freire,da Costa, Marcela Oliveira Legramanti,Pavani, Thais Fernanda Amorim,Xander, Patrícia,Geraldo, Mariana Marques,Mengarda, Ana,de Moraes, Josué,Rando, Daniela Gon?ales Galasse
, (2018/09/13)
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: 46.63μM; SI: 26.11) and 4 (IC50: 53.12μM; 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.
