Fluorine-containing aryloxyethyl thiocyanate derivatives are potent inhibitors of Trypanosoma cruzi and Toxoplasma gondii proliferation

Abstract

As a part of our project aimed at developing new safe chemotherapeutic and chemoprophylactic agents against tropical diseases, fluorine-containing drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (1) were designed, synthesized and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas' disease) and Toxoplasma gondii, the etiological agent of toxoplasmosis. This thiocyanate derivative had previously proven to be an effective agent against T. cruzi proliferation. Fluorine-containing ©2007 Elsevier Science Ltd. All rights reserved. *Corresponding author. Tel.: +54 11 4576 3346; fax: +54 11 4576-3385; e-mail: E-mail: jbr@qo.fcen.uba.ar . Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. It multiplies within the insect gut as an epimastigote form and is spread as a non-dividing metacyclic trypomastigote from the insect feces by contamination of intact mucosa or wounds produced by the blood-sucking activity of the vector. In the mammalian host, T. cruzi proliferates as the intracellular amastigote form, which is next released into the bloodstream as a non-dividing highly infective trypomastigote that can either invade other tissues or can infect the respective Chagas' disease vectors closing the cycle. 3-5 Transmission via the placenta or by blood transfusion is the responsible mechanism for the occurrence of Chagas' disease in developed ctries where the disease is not endemic. 6,7 NIH Public AccessToxoplasmosis is caused by Toxoplasma gondii, a complex eukaryotic parasite that has adopted an essential intracellular survival strategy. 5,8 Most of T.gondii infections are asymptomatic. There are two asexual forms that can cause disease in humans. The tachyzoite form, which can invade all types of cells and divides rapidly leading to cell death, and the bradyzoite form that divides slowly and forms cysts in muscle and brain. 9The existing chemotherapy either for Chagas' disease or for toxoplasmosis remains deficient. The chemotherapy for Chagas' disease is based on two drugs empirically discovered, nifurtimox, now discontinued, and benznidazole. Although both of these compounds are able to cure at least 50% of recent infections as indicated by the disappearance of symptoms, and reduction of parasitemia and serology, they present severe side effects. 10,11 The standard treatment against T. gondii infections consists in the combination of pyrimethamine, which inhibits the enzymatic activity of dihydrofolate reductase, and sulfadiazine, whose target is dihydropteroate synthetase. 12 This thera...

Design, synthesis and biological evaluation of WC-9 analogs as antiparasitic agents

“…The tetrahydropyranyl precursor 10 of 13 was devoid of biological activity against T. cruzi (amastigotes) proliferation. This observation was not in agreement with our previous results in other closely related compounds, where the biological activity of WC-9 analogues correlated quite well with the activity exhibited by their synthetic tetrahydropyranyl ether precursors when bonded to the same aromatic skeleton [22,23,32]. Compound 13 was also a potent inhibitor of T. gondii (tachyzoites) growth possessing an ED 50 values at the very low micromolar level (2.0 μM).…”

“…We have established a rigorous SAR studies on WC-9 chemical structure finding that the phenoxyethyl thiocyanate moiety, which is colored in red in Figure 1, can be considered as the structure of the pharmacophore [21-23,31,32]. However, pharmacokinetic properties of this representative drug still should be improved.…”

“…For example, the introduction of a fluorine atom at the B ring of WC-9 gives rise to compounds 2 and 3 , which have estimated log P values of 4.71 versus log P of 4.51 for WC-9 , indicating a better distribution between water/octanol. In fact, these two drugs, 2 and 3 , are significantly more potent than WC-9 [32]. …”

Aryloxyethyl Thiocyanates Are Potent Growth Inhibitors of Trypanosoma cruzi and Toxoplasma gondii

“…In fact, both of these compounds, 2 and 3 , are significantly more potent than WC-9 in in vitro assays (Figure 1). [23] …”

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

“…It has been found that growth inhibition of T. cruzi epimastigotes induced by 4-Phenoxyphenoxyethyl thiocyanate also known as WC-9 was associated with a reduction in the content of the parasite's endogenous sterols due to a specific blockade of their de novo synthesis at the level of squalene synthase [73]. Previous studies on WC-9 have indicated that structural variation at the B ring had no influence on biological action [74,74], it was thought that the introduction of a fluorine atom at the B ring would benefit biological activity.…”