BackgroundThere 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.MethodsThe 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.ResultsFour 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (10.1186/s40409-018-0163-x) contains supplementary material, which is available to authorized users.
Background:
Schistosomiasis is a neglected disease, which affects millions of people in developing
countries. Its treatment relies on a single therapeutic alternative, the praziquantel. This situation
may lead to drug resistance which, in turn, made urgent the need for new antischistosomal agents. Nacylhydrazones
are usually explored as good antimicrobial agents, but the vanillin-related N-acylhydrazones
have never been tested by their antiparasitic potential.
Objective:
Herein, we report the synthesis of seven analogues, three of them unpublished, their biological
investigation against Schistosoma mansoni and Target Fishing studies.
Methods:
The compounds were synthesized following classical synthetical approaches. The anthelmintic
potential was assessed as well as their cytotoxicity profile. Confocal laser scanning microscopy and target
fishing study were performed to better understand the observed antischistosomal activity.
Results:
Compound GPQF-407 exhibited good antischistosomal activity (47.91 µM) with suitable selectivity
index (4.14). Confocal laser scanning microscopy revealed that it triggered severe tegumental destruction
and tubercle disintegration. Target fishing studies pointed out some probable targets, such as the
serine-threonine kinases, dihydroorotate dehydrogenases and carbonic anhydrase II.
Conclusion:
The GPQF-407 was revealed to be a promising antischistosomal agent which, besides presenting
the N-acylhydrazone privileged scaffold, also could be easily synthesized on large scales from
commercially available materials.
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