Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation

As a part of our project directed at the search of new chemotherapeutic age nts against American trypanosomiasis (Chagas' disease), several drugs posse ssing the 4-phenoxyphenoxy skeleton and other closely related structures em ploying the thiocyanate moiety as polar end group were designed, synthesize d, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were en visioned bearing in mind the potent activity shown by 4-phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC5 0 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the desi gned compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons , namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-m ethyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were s hown to be very potent antireplicative agents against T. cruzi. On the othe r hand, conformationally restricted analogues as well as branched derivativ es at the aliphatic side chain were shown to be moderately active against T . cruzi growth, The biological activity of drugs bearing the thiocyanate gr oup correlated quite well T-vith the activity exhibited by their normal pre cursors, the tetrahydropyranyl ether derivatives, when bonded to the same n onpolar skeleton. Compounds having the tetrahydropyranyl moeity as polar en d were proportionally much less active than sulfur-containing derivatives i n all cases. Drugs 47 and 72 also resulted to be very active against the am astigote form of the parasite growing in myoblasts; however, they were slig htly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dith io derivative 15 was toxic for myoblasts.