Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents

Hernandes, Marcelo Zaldini; Rabello, Marcelo Montenegro; Leite, Ana Cristina Lima; Cardoso, Marcos Veríssimo de Oliveira; Moreira, Diogo Rodrigo Magalhães; Brondani, Dalci José; Simone, C. A. De; Reis, Luiza Campos; Souza, M. A.; Pereira, Valéria Rêgo Alves; Ferreira, Rafaela Salgado; McKerrow, James H.

doi:10.1016/j.bmc.2010.09.056

Cited by 51 publications

(24 citation statements)

References 53 publications

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“…To date, a number of cysteine protease inhibitors have been developed using a variety of reactive functional groups 31 , also referred to as "warheads, " including aldehydes 20 , fluoromethyl ketones 21 , nitriles 32 , α-ketoesters, amides, and acids 33 , tetrafluorophenoxymethyl ketones 34 , epoxysuccinates 35 , thiosemicarbazones 36 , hydrazone derivatives 37,38 , vinyl sulfones 39 and allyl sulfones 40 . These warheads are attached to either a peptidyl or peptidomimetic scaffold 16,41 .…”

Section: Research Articlementioning

confidence: 99%

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

Fennell

Warren

Chung

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Research Articlementioning

confidence: 99%

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

Fennell

Warren

Chung

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Among these, 3, 4-dichlorophenyl thiosemicarbazone (26) is one of the most potent cruzipain inhibitor [61]. Recently, thiazolidinone derivatives (27) were identified as strong antiparasitic compounds (Figure 7) [62,63].…”

Section: Chagas Disease -Basic Investigations and Challenges 160mentioning

confidence: 99%

New Approaches for Chagas’ Disease Chemotherapy

Liñares¹

2018

Chagas Disease - Basic Investigations and Challenges

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The latest advances concerning drug design and chemotherapy development to combat the Chagas' disease are discussed. This chapter is based on the metabolic differences between the pathogenic parasite and mammal hosts that led to the progress in the search for novel metabolic pathways in parasites that may be essential for parasite's survival but with no counterpart in the host. There is a considerable amount of work in the search of more promising molecular targets for drug design. However, the chemotherapy for this disease remains unsolved. It is based on old and fairly not specific drugs associated with long-term treatments, severe side effects, drug resistance, and different strains' susceptibility. Herein, a thorough analysis of selected molecular targets is described in terms of their potential usefulness for drug design. Therefore, rational approaches to the chemotherapeutic control of American trypanosomiasis describing some useful metabolic pathways are covered. Enzymes involved in ergosterol biosynthesis (squalene synthase, HMG-CoA reductase, farnesyl diphosphate synthase (FPPS), sterol 24-methyltransferase, and sterol 14α-demethylase), trypanothione system (glutathionyl-spermidine synthetase, trypanothione synthetase, and trypanothione reductase), cysteine proteases, transsialidase, and so on are discussed. The design of specific inhibitors of these metabolic activities as possible means of controlling the parasites without damaging the hosts is presented. Different compounds can behave as TryR inhibitors when turning into reactive radical speciesthrough the reduction single-electron step [83,91]. Within these structures, 1, 4 naphthoquinones and nitrofurans have been largely studied [92,93]. The most potent derivative of 1,4 naphthoquinone was a quinone-coumarin hybrid [51] despite showing toxicity against rat skeletal myoblasts [94].Between nitrofurans compounds, several 5-nitrofuroic acid derivatives have been synthesized and evaluated against T. cruzi. The best compound was 5-nitro-furan-2-carboxylic acid dibenzyl amide [52], which it significantly increased the trypanocidal nifurtimox activity being TryTR your molecular target [95]. ConclusionsCurrently, the chemotherapy of American trypanosomiasis remains a serious problem in the field of neglected tropical diseases. There are no vaccines, and chemotherapy is limited to old drugs, which present important drawbacks. Taking into account that this disease is associated with poor populations and bad housing conditions, pharmaceutical companies have no economic motivations. Therefore, all efforts to the development of new drugs must be made by academic and/or governmental institutions and new chemotherapies are needed urgently. In order to search new, safer and efficient drugs for the Chagas' treatment, an overview of possible molecular targets based on specific features of the biochemistry of Trypanosoma cruzi was given. Although there are numerous potentially valid targets, only the more representative ones were discussed here. Furthermore, some of t...

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“…[17,18] Based on this, our research group has been investigating cruzain-inhibiting hydrazones to obtain novel and potent anti-T. cruzi agents. At least five distinct classes were investigated: thiosemicarbazones, [19] N-acylhydrazones, [20,21] thiazolidinones [22][23][24] and their transition metal complexes. [25] Within the thiazolidinone class of compounds, we identified compound 18 after examining the importance of modifications at every atom of the thiazolidinic ring ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Structural Design, Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐Trypanosoma cruzi Activity

et al. 2013

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Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.

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Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents

Cited by 51 publications

References 53 publications

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

New Approaches for Chagas’ Disease Chemotherapy

Structural Design, Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐Trypanosoma cruzi Activity

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