Trypanosoma cruzi nitroreductase: Structural features and interaction with biological membranes

Cirqueira, Marília L.; Bortot, Leandro Oliveira; Bolean, Maytê; Aleixo, Mariana A.A.; Luccas, Pedro H.; Costa-Filho, Antonio J.; Ramos, Ana Paula; Ciancaglini, Pietro; Nonato, Maria Cristina

doi:10.1016/j.ijbiomac.2022.09.073

Cited by 7 publications

(14 citation statements)

References 51 publications

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“…When compared to their 1-benzyl analogs, substituted 1-phenyl piperazines were significantly more potent (6-10 fold) against T. cruzi. [48] From this study [49] it was found that when a heteroaryl ring containing nitrogen(s) was used in place of the 1-phenyl group, the antichagasic activity was significantly reduced. The antichagasic activity of 1-pyridino-/1-pyrimidino-piperazines was influenced by the position of the nitrogen(s) in the 1-phenylgroup.…”

Section: Nitroreductasementioning

confidence: 87%

“…[47] It is worth to note that nitroreductase from T. cruzi has not been crystalized yet, although there is an important report where the three-dimensional structure of TcNTR has been predicted. [48] In this part of the review, we are going to discuss about the work of Papadopoulou and her groups. They worked on nitrotriazoles-based compound most of the time, over six years in roll, from 2011 until 2016.…”

Section: Nitroreductasementioning

confidence: 99%

“…As a result, it is hypothesized that because the cyano‐group can act as a hydrogen bond acceptor in addition to its excellent inductive properties, it might interact negatively with type I Tc‐NTR. When compared to their 1‐benzyl analogs, substituted 1‐phenyl piperazines were significantly more potent (6–10 fold) against T. cruzi [48] …”

Section: Introductionmentioning

confidence: 99%

“…It is worth to note that nitroreductase from T. cruzi has not been crystalized yet, although there is an important report where the three‐dimensional structure of TcNTR has been predicted [48] …”

Section: Introductionmentioning

confidence: 99%

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The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

Gomes Pernichelle,

Tavares Marcelino Alves,

Massarico Serafim

et al. 2023

ChemistrySelect

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Chagas disease (CD) is one of extremely Neglected Tropical Diseases (NTD) that have been challenging the health of billions of people in the world. Despite being a threat worldwide many of these diseases have a scarce chemotherapeutic armamentarium and the drugs currently used are not effective because of several reason, such as drug resistance, serious side‐effects, among others. Only two drugs are currently available for CD therapeutics, and they are not active in the chronic phase of the diseases. Considering the huge necessity of drugs for this parasitosis, the search for either new or better drugs than those used, many research groups have been involved in this investigation. New scaffolds can be used with this purpose and piperazine is one of them. Since it has many chemical, pharmacological and pharmacokinetics advantages, including multitarget activity, this group has been often used in CD. In this review, which the role of piperazine group in the structure‐activity of some important targets for T. cruzi, as cruzain, trypanothione reductase, Fe‐superoxide dismutase, and nitroreductase as well, is comprehended, several examples have been given to inspire researchers to optimize either hit or lead compounds against T. cruzi.

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Section: Nitroreductasementioning

confidence: 87%

Section: Nitroreductasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

Gomes Pernichelle,

Tavares Marcelino Alves,

Massarico Serafim

et al. 2023

ChemistrySelect

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“…TcNTR was expressed and purified according to the protocol previously described. [36] Enzyme activity was measured by monitoring the oxidation of NADH at 340 nm (ε = 6.220 M −1 cm −1 ). The reaction mixture contained 50 mM Tris (Sigma-Aldrich ® ) pH 7.5, 0.1% Triton X-100 (Sigma-Aldrich ® ), 50 μM of NADH (Sigma-Aldrich ® ), and 10 or 25 μM of tested compound.…”

Section: Antitrypanosomal Assaymentioning

confidence: 99%

Repurposing of 5‐nitrofuran‐3,5‐disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents

Carvalho

Neves

Portapilla

et al. 2022

Archiv der Pharmazie

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Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease. 5-Nitrofuran-isoxazole analogs were synthesized by cycloaddition reactions [3+2] between chloro-oximes and acetylenes in satisfactory yields. We analyzed the structure-activity relationship of the analogs based on Hammett's and Hansch's parameters. The 5-nitrofuran-isoxazole analogs exhibited relevant in vitro antitrypanosomal activity against the amastigote forms of T. cruzi. Analog 7s was the trending hit of the series, showing an IC 50 value of 40 nM and a selectivity index of 132.50. A possible explanation for this result may be the presence of an electrophile near the isoxazole core. Moreover, the most active analogs proved to act as an in vitro substrate of type I nitroreductase rather than the cruzain, enzymes commonly investigated in molecular target studies of CD drug discovery. These findings suggest that 5-nitrofuran-isoxazole analogs are promising in the studies of agents for CD treatment.

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New 2‐nitroimidazole‐N‐acylhydrazones, analogs of benznidazole, as anti‐Trypanosoma cruzi agents

Pitombeira,

Júnior,

Murta

et al. 2024

Archiv der Pharmazie

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Chagas disease is a neglected tropical parasitic disease caused by the protozoan Trypanosoma cruzi. Worldwide, an estimated 8 million people are infected with T. cruzi, causing more than 10,000 deaths per year. Currently, only two drugs, nifurtimox and benznidazole (BNZ), are approved for its treatment. However, both are ineffective during the chronic phase, show toxicity, and produce serious side effects. This work aimed to obtain and evaluate novel 2‐nitroimidazole‐N‐acylhydrazone derivatives analogous to BNZ. The design of these compounds used the two important pharmacophoric subunits of the BNZ prototype, the 2‐nitroimidazole nucleus and the benzene ring, and the bioisosterism among the amide group of BNZ and N‐acylhydrazone. The 27 compounds were obtained by a three‐step route in 57%–98% yields. The biological results demonstrated the potential of this new class of compounds, since eight compounds were potent and selective in the in vitro assay against T. cruzi amastigotes and trypomastigotes using a drug‐susceptible strain of T. cruzi (Tulahuen) (IC50 = 4.3–6.25 µM) and proved to be highly selective with low cytotoxicity on L929 cells. The type I nitroreductase (TcNTR) assay suggests that the new compounds may act as substrates for this enzyme.

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Trypanosoma cruzi nitroreductase: Structural features and interaction with biological membranes

Cited by 7 publications

References 51 publications

The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

Repurposing of 5‐nitrofuran‐3,5‐disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents

New 2‐nitroimidazole‐N‐acylhydrazones, analogs of benznidazole, as anti‐Trypanosoma cruzi agents

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