Design, Synthesis and Biological Evaluation of Aryloxyethyl Thiocyanate Derivatives against Trypanosoma cruzi

ELHALEM, ELEONORA; BAILEY, BRIAN N.; DOCAMPO, ROBERTO; UJVÁRY, ISTVÁN; SZAJNMAN, SERGIO HERNÁN; RODRIGUEZ, JUAN BAUTISTA

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Lugar: Columbus, Ohio, USA; Año: 2002 vol. 45 p. 3984 - 3999

0022-2623

   As a continuation of our project aimed at the search for new 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 of this disease, the hemoflagellated protozoan Trypanosoma cruzi. This thiocyanate derivative had 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 showed by 11, 23, 38, 53, 90, 99 and 117 against the epimastigote forms of the parasite. All of them exhibited IC50 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 IC50 values of 3.3 mM. 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 to be a promising drug because was also very effective against amastigotes, the clinically more relevant form of the parasite. This compound was three-fold more potent than 4, while 11 showed nearly the same activity than 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 almost devoid of antiparasitic activity. Compound 43 is an interesting example of an effective antichagasic agent that presents excellent prospective not only as a lead drug but also to be used for further in vivo studies.