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

 

Carina Agostinho Rodrigues¹, Paloma Freire dos Santos¹, Marcela Oliveira Legramanti da Costa¹, Thais Fernanda Amorim Pavani¹, Patrícia Xander², Mariana Marques Geraldo², Ana Mengarda³, Josué de Moraes³, Daniela Gonçales Galasse Rando

 

1 Chemical 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

2 Laboratory 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.

3 Research Group of Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 88, Guarulhos, SP 07020-071, Brazil.

 

ABSTRACT

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 amazonensisas 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.

 

Keywords: 2-aminothiazoles; Antikinetoplastids; Antileishmanial; Cutaneous; Target fishing

 

Received: April 26, 2018.

Accepted: August 28, 2018.

 

Correspondence: dgrando@unifesp.br

 

Authors' contributions

The authors contributed equally to the final version of the manuscript. CAR, PFdS, MOLdC, and TFAP developed the synthetic, structural and activity relationships and molecular modeling studies under the supervision of Dr. DGGR. Dr. PX and MMG were in charge of both the antileishmanial assays and the cytotoxicity assay against THP-1 and L929 cell lines. Dr. JdM and AM developed the cytotoxicity assays on Vero cells. All authors read and approved the final manuscript.

 

Competing interests

The authors declare that they have no competing interests.