Design, Synthesis, and Biological Evaluation of Aryloxyethyl Thiocyanate Derivatives againstTrypanosoma cruzi

Abstract

As a continuation of our project aimed at the search for new and safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas' disease), several drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (4) were designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. This thiocyanate derivative was previously shown to be an effective and potent agent against T. cruzi proliferation. Several drugs possessing thiocyanate groups proved to be effective growth inhibitors of T. cruzi growth. Among the designed compounds, it is important to point out the extremely potent activity shown by 11, 23, 38, 53, 90, 99, and 117 against the epimastigote forms of the parasite. All of them exhibited IC(50) values in the low micromolar range, and these values were comparable with those presented by our lead drug 4 and ketokonazole, a well-known antiparasitic agent. The activity displayed by the nitrogen-containing derivative 90 was very promising with IC(50) values of 3.3 microM. Several other thiocyanate derivatives also proved to be very potent inhibitors of the multiplication of T. cruzi epimastigotes, such as compounds 28, 33, 43, 48, 56, 61, 66, 71, 76, and 124. Compound 43 resulted in being a promising drug because it was also very effective against amastigotes, the clinically more relevant form of the parasite. This compound was 3-fold more potent than 4, while 11 showed nearly the same activity as our lead drug against intracellular T. cruzi. It was very surprising that the experimental juvenoid 124, although fairly devoid of activity against epimastigotes, was very effective against intracellular amastigotes growing in myoblasts. The rest of the designed compounds showed a broad degree of inhibitory action, from moderately active drugs to drugs almost devoid of antiparasitic activity. Compound 43 is an interesting example of an effective antichagasic agent that presents excellent prospectives not only as a lead drug but also to be used for further in vivo studies.

A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds

“…The antitrypanosomals considered on this study are representatives of families with diverse structural patterns. [29][30][31][32][33][34][35][36][37][38] Figure 2 shows the whole active set collected from the literature for this work. The selected inactive group included antivirals, sedative/hypnotics, diuretics, anticonvulsivants, hemostatics, oral hypoglycemics, antihypertensives, antihelminthics, anticancer compounds as well as some other kinds of drugs, guaranteeing at the same time a great structural variability.…”

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

“…Therefore, it is expected that the next planned analogs should contain lipophilic substituents on meta and para positions. There are important scientific studies that can support a rational design of new SQS inhibitors using molecular modeling [76,77] and structure activity relationship [71,78,79].…”

Selection of Molecular Targets for Drug Development Against Trypanosomatids

“…Despite the fact that most SQS inhibitors tested in the parasite also block the mammalian host enzyme, this inhibition is tolerable in mammals. In addition, it has been possible to develop specific antiparasitic SQS inhibitors (Orenes Lorente et al 2005 ;Sealey-Cardona et al 2007 ), such as aryloxylethyl thiocyanates (WC-9) (Elhalem et al 2002 ; ) and 2-alkylaminoethyl-1,1-bisphosphonic acids (Rodrigues-Poveda et al 2012 ). Another enzyme in the parasitic sterol biosynthesis pathway is squalene epoxidase (EC1.4.99.7) that converts squalene to 2,3 oxidosqualene.…”