Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities

Mello, Francisco do Vale Chaves e; Quaresma, Bruna Maria Castro Salomão; Pitombeira, Marcelly Cristina Resende; Brito, Monique Araújo de; Farias, Patrícia Pereira; Castro, Solange L. de; Salomão, Kelly; Carvalho, Alcione Silva de; Paula, Jéssica Isis Oliveira; Nascimento, Suelen de Brito; Cupello, Mauricio Peixoto; Paes, Márcia Cristina; Boechat, Núbia; Felzenszwalb, Israel

doi:10.1016/j.ejmech.2019.111887

Cited by 11 publications

(1 citation statement)

References 58 publications

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“…According to these findings, it is noteworthy to point out that nitroheterocycles are still considered as a tempting group of molecules to be explored for the identification of novel CD treatments (Patterson and Fairlamb, 2018). Several families of synthetic compounds that contain nitro groups in their scaffolds and also commercialized drugs identified by repurposing strategies, such as the 5-nitroimidazole metronidazole, have been recently proposed as putative anti- T. cruzi agents, according to the promising activity they achieved in different experimental models of the disease, both in vitro and in vivo (Simões-Silva et al ., 2017; Thompson et al ., 2017; Almeida et al ., 2018; Arias et al ., 2018; Leite et al ., 2018; Palace-Berl et al ., 2018; Chaves e Mello et al ., 2020). Nevertheless, toxicity issues are usually attributed to this kind of compounds (Patterson and Wyllie, 2014) and thus, it is mandatory to discard any potential risk associated to the presence of a nitro group in the antichagasic prototype.…”

Section: Introductionmentioning

confidence: 99%

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Fonseca-Berzal¹,

Silva²,

Batista³

et al. 2020

Parasitology

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In previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.

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Section: Introductionmentioning

confidence: 99%

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Fonseca-Berzal¹,

Silva²,

Batista³

et al. 2020

Parasitology

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Drug re‐engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery

Reddy

Sinha

Kumar

et al. 2022

Archiv der Pharmazie

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The prevalence of tuberculosis (TB) remains the leading cause of death from a single infectious agent, ranking it above all other contagious diseases. The problem to tackle this disease seems to become even worse due to the outbreak of SARS-CoV-2.Further, the complications related to drug-resistant TB, prolonged treatment regimens, and synergy between TB and HIV are significant drawbacks. There are several drugs to treat TB, but there is still no rapid and accurate treatment available.Intensive research is, therefore, necessary to discover newer molecular analogs that can probably eliminate this disease within a short span. An increase in efficacy can be achieved through re-engineering old TB-drug families and repurposing known drugs.These two approaches have led to the production of newer classes of compounds with novel mechanisms to treat multidrug-resistant strains. With respect to this context, we discuss structural aspects of developing new anti-TB drugs as well as examine advances in TB drug discovery. It was found that the fluoroquinolone, oxazolidinone, and nitroimidazole classes of compounds have greater potential to be further explored for TB drug development. Most of the TB drug candidates in the clinical phase are modified versions of these classes of compounds. Therefore, here we anticipate that modification or repurposing of these classes of compounds has a higher probability to reach the clinical phase of drug development. The information provided will pave the way for researchers to design and identify newer molecular analogs for TB drug development and also broaden the scope of exploring future-generation potent, yet safer anti-TB drugs.

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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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Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities

Cited by 11 publications

References 58 publications

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Drug re‐engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery

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

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