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

Abstract

As a part of our project aimed at searching for 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 and were slightly more potent than our lead WC-9. For example, two trifluoromethylated derivatives exhibited ED50 values of 10.0 and 9.2 μM against intracellular T. cruzi, whereas they showed potent action against tachyzoites of T. gondii (ED50 values of 1.6 and 1.9 μM against T. gondii). In addition, analogues of WC-9 in which the terminal aryl group is in the meta position 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, which suggests that a para-phenyl substitution pattern is not necessary for biological activity.

Keywords: antiparasitic agents; biological activity; chemotherapeutic agents; inhibitors; structure-activity relationships.

Figure 1

Chemical structure of WC-9 (compound 1) and other closely related analogues.

Scheme 1

Reagents and conditions: a) Br(CH₂)₂OTHP, KOH, DMSO, rt, 24 h, 96%; b) H₂, Pd/C, EtOAc, rt, 4 h, 73%; c) 1-iodo-3-(trifluoromethyl)benzene or 1-iodo-4-(trifluoromethyl)benzene, 5% CuI, 10% picolinic acid, K₃PO₄, DMSO, 90 °C, 36 h; d) PPTS, MeOH, rt, 24 h; e) TsCl, Py, 0 °C, 4h; e) KSCN, DMF, 80 °C, 48 h.

Scheme 2

Reagents and conditions: a) 2-bromonaphtalene, 5% CuI, 10% picolinic acid, K3PO4, DMSO, 90 °C, 24 h, 18%; b) PPTS, MeOH, rt, 4 h, 97%; c) ClTs, py, rt, 4 h, 67%; d) KSCN, DMF, 100 °C, 3 h, 43%; e) 1-bromonaphtalene, 5% CuI, 10% picolinic acid, K₃PO₄, DMSO, 90 °C, 24 h, 29%; f) PPTS, MeOH, rt, 4 h, 92%;. g) ClTs, py, rt, 4 h, 91%;.h) KSCN, DMF, 100 °C, 3 h, 43%.

Scheme 3

Reagents and conditions: a) 2-hydroxypyridine (1.2 equiv.) 5% CuI, 10% picolinic acid, K₃PO₄, DMSO, 80 °C, 24 h, 48%; b) PPTs, MeOH, rt, 16 h, 60%; c) ClTs, py, 0 °C, then, rt, 90%; d) KSCN, DMF, 100 °C, 61%.

Scheme 4

Reagents and conditions: a) 5% CuI, 10% picolinic acid, K₃PO₄, DMSO, 80 °C, 24 h; b) PPTs, MeOH, rt, 16 h; c) ClTs, py, 0 °C, 6 h; d) KSCN, DMF,100 °C, 6 h.

Scheme 5

Reagents and conditions: a) 5% CuI, 10% picolinic acid, K₃PO₄, DMSO, 80 °C, 24 h; b) PPTs, MeOH, rt, 16 h; c) NBS, PPh₃, CH₂Cl₂, 0° C, 24%; d) ClTs, py, 0 °C, 6 h; e) KSCN, DMF, 100 °C, 6 h.

Scheme 6

Reagents and conditions: a) NaN₃, DMF, 100 °C, 6 h, 35%.

Scheme 7

Reagents and conditions: a) KOH, BrCH₂CH₂OTHP, DMSO, rt, 16 h, 46%; b) PPTs, MeOH, rt, 16 h, 70%; c) ClTs, py, 0 °C, 6 h, 84%; d) KSCN, DMF, 100 °C, 6 h, 75%.

Scheme 8

Reagents and conditions: a) KOH, BrCH₂CH₂OTHP, DMSO, rt, 16 h, 31%; b) PPTs, MeOH, rt, 16 h, 46%; ClTs, py, 0 °C, 6 h, 69%; d) KSCN, DMF, 100 °C, 6 h, 42%.