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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 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 μM. 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.

Registro:

Documento: Artículo
Título:Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi
Autor:Elhalem, E.; Bailey, B.N.; Docampo, R.; Ujváry, I.; Szajnman, S.H.; Rodriguez, J.B.
Filiación:Departamento de Química Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, RA-1428 Buenos Aires, Argentina
Laboratory of Molecular Parasitology, Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802, United States
Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary
Palabras clave:4 phenoxyphenoxyethylthiocyanate; ketoconazole; thiocyanic acid derivative; unclassified drug; amastigote; antiprotozoal activity; article; Chagas disease; chemoprophylaxis; drug design; drug potency; drug structure; drug synthesis; epimastigote; IC 50; nonhuman; Trypanosoma cruzi; Animals; Structure-Activity Relationship; Thiocyanates; Trypanocidal Agents; Trypanosoma cruzi
Año:2002
Volumen:45
Número:18
Página de inicio:3984
Página de fin:3999
DOI: http://dx.doi.org/10.1021/jm0201518
Título revista:Journal of Medicinal Chemistry
Título revista abreviado:J. Med. Chem.
ISSN:00222623
CODEN:JMCMA
CAS:ketoconazole, 65277-42-1; Thiocyanates; Trypanocidal Agents
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v45_n18_p3984_Elhalem

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  • note

Citas:

---------- APA ----------
Elhalem, E., Bailey, B.N., Docampo, R., Ujváry, I., Szajnman, S.H. & Rodriguez, J.B. (2002) . Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi. Journal of Medicinal Chemistry, 45(18), 3984-3999.
http://dx.doi.org/10.1021/jm0201518
---------- CHICAGO ----------
Elhalem, E., Bailey, B.N., Docampo, R., Ujváry, I., Szajnman, S.H., Rodriguez, J.B. "Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi" . Journal of Medicinal Chemistry 45, no. 18 (2002) : 3984-3999.
http://dx.doi.org/10.1021/jm0201518
---------- MLA ----------
Elhalem, E., Bailey, B.N., Docampo, R., Ujváry, I., Szajnman, S.H., Rodriguez, J.B. "Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi" . Journal of Medicinal Chemistry, vol. 45, no. 18, 2002, pp. 3984-3999.
http://dx.doi.org/10.1021/jm0201518
---------- VANCOUVER ----------
Elhalem, E., Bailey, B.N., Docampo, R., Ujváry, I., Szajnman, S.H., Rodriguez, J.B. Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi. J. Med. Chem. 2002;45(18):3984-3999.
http://dx.doi.org/10.1021/jm0201518