Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity

Serafim, Ricardo Augusto Massarico; Gonçalves, José Eduardo; Souza, Felipe Pereira de; Loureiro, Ana Paula de Melo; Storpirtis, Sílvia; Krogh, Renata; Andricopulo, Adriano D.; Dias, Luiz C.; Ferreira, Elizabeth Igne

doi:10.1016/j.ejmech.2014.05.077

Cited by 46 publications

(12 citation statements)

References 29 publications

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“…In molecular docking analyses, the Cz structure 1U9Q with the ligand 186 (Table 1), a benzyl ester, was used. This was because in other studies, relevant interactions have been shown with amino acids of the catalytic triad (Cys25, His159, and Asn175) and with the amino acids Gln19, Asp158, Trp177, and Gly66, which have been reported in interactions showing a large series of hydrazone derivatives and competitive inhibitors of Cz [4,19,24]. With the ProteinsPlus server and the DoGSiteScorer tool, the binding site of 1U9Q was identified (Figure 2a).…”

Section: Resultsmentioning

confidence: 83%

“…Other authors state that hybrids of N -acylhydrazone and furoxane are active in amastigotes of T. cruzi . Additionally, this class of compounds, by permeability screening in Caco-2 cells and cytotoxicity assays in human cells, showed less cytotoxicity, good permeability, and a higher selectivity index than the reference drug benznidazole [19]. Additionally, the N -acylhydrazone moiety is considered a privileged structure in medicinal chemistry, since it has the potential to interact with different biological targets, including the T. cruzi cysteine protease [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors

Herrera-Mayorga

Lara-Ramírez

Chacón-Vargas

et al. 2019

IJMS

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Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 μM) and trypomastigote (IC50 = 166.21 ± 14.5 μM and 185.1 ± 8.5 μM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

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Section: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors

Herrera-Mayorga

Lara-Ramírez

Chacón-Vargas

et al. 2019

IJMS

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“…Com o sequenciamento do genoma do T. cruzi, foi possível identificar vários alvos biológicos promissores, sendo a maioria deles de enzimas (MAGALHAES MOREIRA et al, 2014). Entre estas enzimas, destaca-se a cruzaína, a principal cisteína protease tripanossomal, está envolvida nos processos de invasão, diferenciação e proliferação do parasita nas células hospedeiras (MASSARICO SERAFIM et al, 2014). A cruzaína é expressa em todos os estágios do desenvolvimento do parasita (CAPUTTO et al, 2011), sendo um alvo específico para o desenvolvimento de novos e seletivos agentes antichagásicos (MASSARICO SERAFIM et al, 2014).…”

Section: Agradecimentosunclassified

“…Entre estas enzimas, destaca-se a cruzaína, a principal cisteína protease tripanossomal, está envolvida nos processos de invasão, diferenciação e proliferação do parasita nas células hospedeiras (MASSARICO SERAFIM et al, 2014). A cruzaína é expressa em todos os estágios do desenvolvimento do parasita (CAPUTTO et al, 2011), sendo um alvo específico para o desenvolvimento de novos e seletivos agentes antichagásicos (MASSARICO SERAFIM et al, 2014). Esta enzima possui o sítio de interação dividido em quatro subsítios (S1, S1 ', S2 e S3) que são direcionados para o desenvolvimento de novos inibidores (MCGRATH et al, 1995).…”

Section: Agradecimentosunclassified

Produção De Catalisadores Para Reação De Fenton Heterogêneo

Pacheco¹,

Souza²,

Santos³

et al. 2019

Atividades De Ensino E De Pesquisa Em Química

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Todo o conteúdo deste livro está licenciado sob uma Licença de Atribuição Creative Commons. Atribuição 4.0 Internacional (CC BY 4.0).O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais.

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“…Cruzain (EC 3.4.22.51), the main cysteine protease of Trypanosoma cruzi , has been broadly explored as a molecular target in Chagas disease drug discovery ( Engel et al, 1998 ; McKerrow, 1999 ; Jose Cazzulo et al, 2001 ; Massarico Serafim et al, 2014 ). This enzyme plays a key role in all stages of the parasite’s life cycle, participating in processes such as nutrition, differentiation, evasion of the host immune system, and invasion of host cells ( Ferreira and Andricopulo, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics

et al. 2022

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Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

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Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity

Cited by 46 publications

References 29 publications

Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors

Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors

Produção De Catalisadores Para Reação De Fenton Heterogêneo

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics

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