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

Author(s)

Rodrigues, Carina Agostinho ^[1] ; dos Santos, Paloma Freire ^[1] ; Legramanti da Costa, Marcela Oliveira ^[1] ; Amorim Pavani, Thais Fernanda ^[1] ; Xander, Patricia ^[2] ; Geraldo, Mariana Marques ^[2] ; Mengarda, Ana ^[3] ; de Moraes, Josue ^[3] ; Galasse Rando, Daniela Goncales ^[1]

Affiliation

^[1] Fed Univ Sao Paulo UNIFESP, Inst Environm Chem & Pharmaceut Sci, Dept Pharmaceut Sci, Chem & Pharmaceut Res Grp, Rua Sao Nicolau 210, 20 Andar, BR-09913030 Diadema, SP - Brazil

^[2] Fed Univ Sao Paulo UNIFESP, Inst Environm Chem & Pharmaceut Sci, Dept Pharmaceut Sci, Lab Cellular Immunol & Biochem Fungi, Rua Sao Nicolau 210, 20 Andar, BR-09913030 Diadema, SP - Brazil

^[3] Univ Guarulhos, Res Grp Neglected Dis, Praca Tereza Cristina 88, BR-07020071 Guarulhos, SP - Brazil

• Document type: Journal article
• Source: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 24, SEP 10 2018.
• Web of Science Citations: 7

Abstract

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 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)

• FAPESP's process: 13/01875-0 - Parallel synthesis, in vitro screening and SAR studies of a nitroderivatives compounds library active against macrophage's pathogens: Mycobacterium tuberculosis NRP forms and Leishmania sp
• Grantee: Daniela Goncales Galasse Rando
• Support Opportunities: Regular Research Grants