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Alvarez, Guzman; Martinez, Jennyfer; Varela, Javier; Birriel, Estefania; Cruces, Eugenia; Gabay, Martin; Leal, Sandra M; Escobar, Patricia; Aguirre-Lopez, Beatriz; Cabrera, Nallely; Tuena de Gomez-Puyou, Marietta; Gomez Puyou, Armando; Perez-Montfort, Ruy; Yaluff, Gloria; Torres, Susana; Serna, Elva; Vera de Bilbao, Ninfa; Gonzalez, Mercedes; Cerecetto, Hugo (2015)

DEVELOPMENT OF BIS-THIAZOLES AS INHIBITORS OF TRIOSEPHOSPHATE ISOMERASE FROM TRYPANOSOMA CRUZI. IDENTIFICATION OF NEW NON-MUTAGENIC AGENTS THAT ARE ACTIVE IN VIVO

Eur J Med Chem 100():246-256
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The neglected disease American trypanosomiasis is one of the major health problems in Latin America. Triosephosphate isomerase from Trypanosoma cruzi (TcTIM), the etiologic agent of this disease, has been proposed as a druggable target. Some bis-benzothiazoles have been described as irreversible inhibitors of this enzyme. On the other hand, new bioactive furane-containing thiazoles have been described as excellent in vivo anti-T. cruzi agents. This encouraged us to design and develop new bis-thiazoles with potential use as drugs for American trypanosomiasis. The bis-thiazol 5, 3,3'-allyl-2,2'-bis[3-(2-furyl)-2-propenylidenehydrazono]-2,2',3,3'-tetrahydro-4,4'-bisthiazole, showed the best in vitro anti-T. cruzi profile with a higher selectivity index than the reference drugs Nifurtimox and Benznidazole against amastigote form of the parasite. This derivative displayed marginal activity against TcTIM however the bis-thiazol 14, 3-allyl-2-[3-(2-furyl)-2-propenylidenehydrazono]-3'-phenyl-2'-(3-phenyl-2-propenylidenehydrazono]-2,2',3,3'-tetrahydro-4,4'-bisthiazole, was an excellent inhibitor of the enzyme of the parasite. The absence of both in vitro mutagenic and in vivo toxicity effects, together with the activity of bis-thiazol 5in vivo, suggests that this compound is a promising anti-T. cruzi agent surpassing the "hit-to-lead" stage in the drug development process. (©)2015 Elsevier Science Ltd. All rights reserved.