Optimization of anti-Trypanosoma cruzi oxadiazoles leads to identification of compounds with efficacy in infected mice

We recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrations. These compounds are easy to synthesize and show a number of clear and interpretable structure-activity relationships (SAR), features that make them attractive to pursue potency enhancement. We present here the structural design, synthesis, and anti-T. cruzi evaluation of new oxadiazoles denoted 5a-h and 6a-h. The design of these compounds was based on a previous model of computational docking of oxadiazoles on the T. cruzi protease cruzain. We tested the ability of these compounds to inhibit catalytic activity of cruzain, but we found no correlation between the enzyme inhibition and the antiparasitic activity of the compounds. However, we found reliable SAR data when we tested these compounds against the whole parasite. While none of these oxadiazoles showed toxicity for mammalian cells, oxadiazoles 6c (fluorine), 6d (chlorine), and 6e (bromine) reduced epimastigote proliferation and were cidal for trypomastigotes of T. cruzi Y strain. Oxadiazoles 6c and 6d have IC50 of 9.5 +/- 2.8 and 3.5 +/- 1.8 mu M for trypomastigotes, while Benznidazole, which is the currently used drug for Chagas disease treatment, showed an IC50 of 11.3 +/- 2.8 mu M. Compounds 6c and 6d impair trypomastigote development and invasion in macrophages, and also induce ultrastructural alterations in trypomastigotes. Finally, compound 6d given orally at 50 mg/kg substantially reduces the parasitemia in T. cruzi-infected BALB/c mice. Our drug design resulted in potency enhancement of oxadiazoles as anti-Chagas disease agents, and culminated with the identification of oxadiazole 6d, a trypanosomicidal compound in an animal model of infection. (C) 2012 Elsevier Ltd. All rights reserved.CNPqCNPqFAPESBFAPESBUniversidade Federal de Pernambuco (UFPE)Universidade Federal de Pernambuco (UFPE)Conselho Nacional de Pesquisas Brasileira (CNPq)Conselho Nacional de Pesquisas Brasileira (CNPq) [478454/2010-4]Fundacao de Amparo as Pesquisas do Estado da Bahia (FAPESB)Fundacao de Amparo as Pesquisas do Estado da Bahia (FAPESB) [6596

Structural Investigation of Anti-Trypanosoma cruzi 2-Iminothiazolidin-4-ones Allows the Identification of Agents with Efficacy in Infected Mice

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one S. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epirnastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.CNPq [471461/2011-3]CAPES [23038.003155/2011-37]FAPESB (PRONEX grant)European Union ChemBioFight [269301]CAPES-Fulbright Foundatio

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent

Submitted by Éder Freyre ([email protected]) on 2017-02-13T13:10:12Z No. of bitstreams: 1 ve_Diogo_Moreira_etal_CPqGM_2014.pdf: 1053015 bytes, checksum: 283a95300677183e0f6d3a26fe6a040c (MD5)Approved for entry into archive by Éder Freyre ([email protected]) on 2017-02-13T16:20:17Z (GMT) No. of bitstreams: 1 ve_Diogo_Moreira_etal_CPqGM_2014.pdf: 1053015 bytes, checksum: 283a95300677183e0f6d3a26fe6a040c (MD5)Made available in DSpace on 2017-02-13T16:20:17Z (GMT). No. of bitstreams: 1 ve_Diogo_Moreira_etal_CPqGM_2014.pdf: 1053015 bytes, checksum: 283a95300677183e0f6d3a26fe6a040c (MD5) Previous issue date: 2015CNPq, FAPESB, FAPEAL e CAPES.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Universidade Federal de Alagoas. Instituto de Química e Biotecnologia. Maceió, AL, Brasil.Universidade Federal de Alagoas. Instituto de Química e Biotecnologia. Maceió, AL, Brasil.Universidade Federal de Alagoas. Instituto de Química e Biotecnologia. Maceió, AL, Brasil.Universidade Federal da Paraíba. Laboratório de Tecnologia Farmacêutica. João Pessoa, PB, Brasil.Universidade Federal da Paraíba. Laboratório de Tecnologia Farmacêutica. João Pessoa, PB, Brasil.Universidade Federal Rural de Pernambuco. Departamento de Química. Recife, PE, Brasil.Universidade Federal Rural de Pernambuco. Departamento de Química. Recife, PE, Brasil.Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil.Universidade Federal de Alagoas. Instituto de Química e Biotecnologia. Maceió, AL, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the β-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol