1,2,4-thiadiazol-5(4<i>H</i>)-ones: a new class of selective inhibitors of <i>Trypanosoma cruzi</i> triosephosphate isomerase. Study of the mechanism of inhibition

Álvarez, Guzmán; Aguirre-López, Beatriz; Cabrera, Nallely; Marins, Eliã B.; Tinoco, Luzineide W.; Batthyány, Carlos; Gómez‐Puyou, Marietta Tuena de; Puyou, Armando Gómez; Pérez‐Montfort, Ruy; Cerecetto, Hugo; González, Mercedes

doi:10.3109/14756366.2012.700928

Cited by 14 publications

(16 citation statements)

References 22 publications

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“…In each compound family, one or two derivatives displayed an excellent ability to inhibit this enzyme, e.g., the [1,2]dithiole-3-thione 5, the 3-propylidene[1,2]dithioles 13 and 16, and [1,2]dithiolium salts 18 and 19. The best inhibitor was thione 5, which had the same potency as 3 ( Figure 1) [11]. Interestingly, excluding derivative 13, no relationship between anti-epimastigote activity, of the most active compounds, and inhibition of TcTIM was observed.…”

Section: Inhibition Of Tctimmentioning

confidence: 95%

“…These are compounds 1 and 2 ( Figure 1A) [14], which, at 25 μM, had high percentages of TcTIM inhibition, 33% and 48%, respectively. These compounds are structurally related to one of our best TcTIM inhibitors, the [1,2,4]thiadiazol-5(4H)-one 3 ( Figure 1B) [11]. On the other hand, the 3-H-1,2-dithiole heterocycle has been previously described as the framework responsible for schistosomicidal activity, e.g., in oltipraz (4, Figure 1C) [15].…”

Section: Introductionmentioning

confidence: 99%

“…This enzyme is involved in the glycolysis pathway of the parasite. We evaluated nearly 300 compounds from our in-house library against TcTIM, identifying good inhibitors [10][11][12][13] and also hits with the ability to act as potential inhibitors, after further structural modifications. Of these hits we identified two compounds with an original framework in the context of anti-trypanosomal agents, the 3H- [1,2]dithiole heterocycles.…”

Section: Introductionmentioning

confidence: 99%

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3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

et al. 2015

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Abstract:The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, OPEN ACCESSMolecules 2015, 20 14596 like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease.

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Section: Inhibition Of Tctimmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

et al. 2015

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“…Recently, we reported 14,18 that it is possible to use chimeras of TcTIM and TbTIM in order to identify the amino acids or amino acid sequences that are involved in a given property of the enzymes. Thus, we examined the effect of compounds 2 and 3 on a TcTIM in which regions 1 (residues 1-35) and 4 (residues 92-119) were replaced by the corresponding regions of TbTIM, namely TcTIM 2,3,5-8 (Figure 5a).…”

Section: The Action Of Compounds 2 and 3 On Different Timsmentioning

confidence: 99%

“…Since both molecules bind to adjacent regions around Cys-118, they could compete for access to the binding site. [14]. c The value in parenthesis corresponds to the IC 50 in mM.…”

Section: Theoretical Calculationsmentioning

confidence: 99%

New chemotypes as Trypanosoma cruzi triosephosphate isomerase inhibitors: a deeper insight into the mechanism of inhibition

Álvarez

Martínez

Aguirre-López

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Context: Triosephosphate isomerase (TIM) is a ubiquitous enzyme that has been targeted for the discovery of new small molecular weight compounds used against Trypanosoma cruzi, the causative agent of Chagas disease. We have identified phenazine and 1,2,6-thiadiazine chemotypes as novel inhibitors of TIM from T. cruzi (TcTIM). Objective: Study the mechanism of TcTIM inhibition by a phenazine derivative and by a 1,2,6-thiadiazine derivative. Methods: We performed biochemical and theoretical molecular docking studies to characterize the interaction of the derivatives with wild-type and mutant TcTIM. Results and conclusion: At low micromolar concentrations, the compounds induce highly selective irreversible inactivation of parasitic TIM. The molecular docking simulations indicate that the phenazine derivative likely interferes with the association of the two monomers of the dimeric enzyme by locating at the dimer interface, while 1,2,6-thiadiazine could act as an inhibitor binding to a region surrounding Cys-118.

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Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity

et al. 2015

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Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC50 value of 86 nm without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases.

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1,2,4-thiadiazol-5(4H)-ones: a new class of selective inhibitors of Trypanosoma cruzi triosephosphate isomerase. Study of the mechanism of inhibition

Cited by 14 publications

References 22 publications

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

New chemotypes as Trypanosoma cruzi triosephosphate isomerase inhibitors: a deeper insight into the mechanism of inhibition

Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity

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