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

Abstract

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.

Synthesis and biological evaluation of thiazole derivatives as LbSOD inhibitors

“…Previous studies have shown that 1,3-thiazole derivatives have leishmanicidal activity 26 and that phthalimide-thiazole derivatives have higher affinity to L. infantum FeSOD than human CuZnSOD 27 . These results suggest the thiazole ring is a suitable scaffold upon which novel SOD inhibitors might be developed.…”

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

“…We verified this potential in the phenotypic trials on L. amazonensis and L. braziliensis ; however, this effect was not seen in promastigotes of L.infantum . The chlorine atom as the substituent in R2 in 2c increased cytotoxicity when compared to 2b by 2.6 times; this increased cytotoxicity profile was also observed with the insertion of one or two chlorine atoms in the 4-Phenyl-1,3-thiazol-4-amines series [ 36 ]. Croft and cols reported that Leishmania species show a significant variation in their sensitivity to established and experimental drugs [ 37 ].…”

GC-MS-Based Metabolomic Profiles Combined with Chemometric Tools and Cytotoxic Activities of Non-Polar Leaf Extracts of Spondias mombin L. and Spondias tuberosa Arr. Cam.

“…Compounds that exhibit about two-fold increased selectivity in tumor cells than in non-tumor cells are promising compounds for mechanism of action studies. 39 The L929 cell line was studied as a normal murine cell line control by Salido et al, 40 verifying that the extracts of L. tridentata were more selective for the tumor cells, indicating possible decreases in side effects when compared to existing drugs in the clinic.…”