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

Abstract

As a part of our project aimed at searching new safe chemotherapeutic agents against parasitic diseases, several compounds structurally related to the antiparasitic agent WC-9 (4-phenoxyphenoxyethyl thiocyanate), which were modified at the terminal phenyl ring, were designed, synthesized and evaluated as growth inhibitors against Trypanosoma cruzi, the etiological agent of Chagas disease and Toxoplasma gondii, the parasite responsible of toxoplasmosis. Most of the synthetic analogues exhibited similar antiparasitic activity being slightly more potent than our lead WC-9. For example, the trifluoromethyl derivatives 15 and 16 exhibited ED50 values of 10.0 μM and 9.2 μM, respectively, against intracellular T. cruzi, whereas they showed potent action against tachyzoites of T. gondii (ED50 values 1.6 μM and 1.9 μM against T. gondii, respectively). In addition, the WC-9 analogues 48 and 61, in which the terminal aryl group was meta with respect to the alkyl chain bearing the thiocyanate group, showed potent inhibitory action against both T. cruzi and T. gondii at the very low micromolar range suggesting that para-phenyl substitution pattern is not necessarily required for biological activity.

Activity of Fluorine‐Containing Analogues of WC‐9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii

“…An interesting structuralv ariation was the replacement of the terminal phenyl group by ap yridyl group, in which the nitrogen atom occupied the 4'' position (compound 31). We have previously synthesized and evaluated the corresponding 2-pyridyl [21] and 3-pyridyl [20] derivatives, so the availability of 31 would complete the corresponding SAR analysis.Astraightforward synthesis of 31 was accomplished by startingf rom 23, [20] which wast reated with 4-hydroxypyridine under typical coupling reactionc onditions to generate 28.O nt reatment with pyridinium 4-toluenesulfonate, 28 was converted into alcohol 29,w hichw as further transformed into 30 by reaction with Nbromosuccinimide and triphenylphosphine [40] in 50 %y ield. On reactionw ith potassium thiocyanate, 30 was transformedi nto the desired compound 31 in 34 %yield (Scheme 2).…”

“…At the present time, there is no computer‐assisted protocol to predict binding of WC‐9 analogues to Tc SQS. However, there are abundant structure–activity relationship (SAR) data available on T. cruzi and T. gondii cells that can be used to facilitate drug design . In addition, there is strong evidence to state that the phenoxyethyl thiocyanate moiety of WC‐9 (Figure ) is the pharmacophore of this family of molecules.…”

“…Additional synthetic derivatives of WC-9 (2-6)a re shown in Figure 1. [15,[17][18][19][20][21] It is interesting to note that T. gondii lacks the mevalonate pathway and uses the essential 1-deoxy-d-xylulose-5-phosphate pathway to make isopentenyl diphosphate and dimethylallyl diphosphate. [22] As T. gondii does not synthesize cholesterol and imports it from the host, [11] it is reasonable to consider that inhibitors of the host SQS could eventually control T. gondii growth.…”

“…cruzi and T. gondii cells that can be used to facilitate drug design. [17][18][19][20][21]35] In addition, there is strong evidence to state that the phenoxyethyl thiocyanate moiety of WC-9 ( Figure 1) is the pharmacophore of this family of molecules. A question that emerges, the answer to which is still pending, is whether the optimum substitution pattern will be at the C4' or C3' position.…”

“…This enzyme catalyzes the first step in sterol biosynthesis, which consists of reductive dimerization of two molecules of farnesyl diphosphate to yield squalene. Additional synthetic derivatives of WC‐9 ( 2 – 6 ) are shown in Figure …”