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

2019 ◽  
Vol 20 (7) ◽  
pp. 1742 ◽  
Author(s):  
Verónica Herrera-Mayorga ◽  
Edgar Lara-Ramírez ◽  
Karla Chacón-Vargas ◽  
Charmina Aguirre-Alvarado ◽  
Lorena Rodríguez-Páez ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Selection Process ◽  
Chronic Phase ◽  
Inhibitory Effect ◽  
Pharmacological Treatments ◽  
Trypanocidal Activity ◽  
Trypanocidal Drugs ◽  
Cruzain Inhibitors

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.

scholarly journals Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

Molecules ◽  
2017 ◽  
Vol 22 (6) ◽  
pp. 1015 ◽  
Author(s):  
Isidro Palos ◽  
Edgar E. Lara-Ramirez ◽  
Julio Cesar Lopez-Cedillo ◽  
Carlos Garcia-Perez ◽  
Muhammad Kashif ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
In Vivo Studies ◽  
Screening In Vitro ◽  
Cruzain Inhibitors

New Trypanosoma cruzi Trypanothione Reductase Inhibitors Identification using the Virtual Screening in Database of Nucleus Bioassay, Biosynthesis and Ecophysiology (NuBBE)

2019 ◽  
Vol 17 (2) ◽  
pp. 138-149
Author(s):  
Nelcí do Carmo Santos ◽  
Vinícius G. da Paixão ◽  
Samuel S. da Rocha Pita
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Conclusive Evidence ◽  
New Drugs ◽  
Trypanothione Reductase ◽  
Efficacy And Safety ◽  
Reductase Inhibitors ◽  
Preclinical Trials

Background: American trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi (T. cruzi) and affects approximately 10 to 12 million, primarily in Latin America. Since its discovery in 1909, there is no effective treatment for its chronic phase, with benzonidazole being the only anti-trypanosoma drug used in Brazil, despite the absence of conclusive evidence to prove its efficacy and safety. Thus, it is necessary to develop new drugs that are more effective and selective against Trypanosoma cruzi. Methods: The T. cruzi enzyme Trypanothione Reductase (TcTR) is a validated target for the discovery of new antiprotozoal compounds and we employed the Virtual Screening technique on the database of Nucleus of Bioassays, Biosynthesis and Ecophysiology (NuBBE), aiming to search for new chemical moieties against T. cruzi. From these we selected the 10 best ligand energies interactions and verified their interaction profile with the main TcTR sites through the AuPosSOM server (https://www.biomedicale.univ-paris5.fr/aupossom). Results and Conclusion: Finally, we analyzed some pharmacokinetics and toxicological information through the servers Aggregator Advisor (http://advisor.bkslab.org), Pred-hERG 4.0 (http://labmol.com.br/predherg) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction) which we expect will be useful in in vitro preclinical trials.</P>

scholarly journals Non-peptidic Cruzain Inhibitors with Trypanocidal Activity Discovered by Virtual Screening and In Vitro Assay

2013 ◽  
Vol 7 (8) ◽  
pp. e2370 ◽  
Author(s):  
Helton J. Wiggers ◽  
Josmar R. Rocha ◽  
William B. Fernandes ◽  
Renata Sesti-Costa ◽  
Zumira A. Carneiro ◽  
...  
Keyword(s):  
Virtual Screening ◽  
In Vitro Assay ◽  
Vitro Assay ◽  
Trypanocidal Activity ◽  
Cruzain Inhibitors

scholarly journals A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Roberto I. Cuevas-Hernández ◽  
Richard M. B. M. Girard ◽  
Sarai Martínez-Cerón ◽  
Marcelo Santos da Silva ◽  
Maria Carolina Elias ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Structural Characteristics ◽  
Chronic Phase ◽  
Human Infection ◽  
Host Cells ◽  
Mammalian Host ◽  
Content Type ◽  
Trypanocidal Drugs

ABSTRACT Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes [IC50(Epi) = 23.1 ± 1.75 μM] and intracellular forms of trypomastigotes [IC50(Tryp) = 8.5 ± 2.9 μM] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenylbenzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs.

scholarly journals Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Solange L. de Castro ◽  
Denise G. J. Batista ◽  
Marcos M. Batista ◽  
Wanderson Batista ◽  
Anissa Daliry ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Public Health Problem ◽  
Term Therapy ◽  
High Morbidity ◽  
Synthetic Compounds ◽  
Natural And Synthetic

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

Regulation of Trypanosoma cruzi infectivity by alpha- and beta-adrenergic agonists: desensitization produced by prolonged treatments or increasing agonist concentrations

Parasitology ◽  
1990 ◽  
Vol 100 (3) ◽  
pp. 429-434 ◽  
Author(s):  
A. Ayala ◽  
F. Kierszenbaum
Keyword(s):  
Trypanosoma Cruzi ◽  
Prolonged Exposure ◽  
Inhibitory Effect ◽  
Tissue Level ◽  
Adrenergic Agonists ◽  
Adrenergic Agonist ◽  
Beta Adrenergic ◽  
Beta Adrenergic Agonists ◽  
Alpha Adrenergic Agonist

SUMMARYWe previously reported that blood forms of Trypanosoma cruzi express alpha- and beta-adrenergic receptors and that binding of specific agonists to these receptors modifies the infective capacity of the parasite in vitro. The present study has revealed that the inhibitory effect of the beta-adrenergic agonist L-isoproterenol and the stimulatory effect of the alpha-adrenergic agonist L-phenylephrine are not produced when the parasite is subjected to prolonged exposure to otherwise effective doses of these agonists or when supraoptimal doses of these agonists are used. We refer to these phenomena as ‘desensitization’ because of their analogy with vertebrate cells becoming desensitized by prolonged exposure to, or relatively high concentrations of, adrenergic agonists. At a constant agonist concentration, T. cruzi desensitization was time-dependent and, when the time of parasite treatment with the agonists was not changed, the higher concentrations of the agonist tested were the most effective in producing desensitization. The reduced infectivity resulting from treatment with optimal doses of L-isoproterenol was accompanied by elevated levels of cyclic adenosine mono- phosphate (cAMP) which were not detectable when L-isoproterenol concentrations producing desensitization were used. This finding implicated cAMP as a likely second signal in the inhibitory mechanisms of this agonist. No significant change in cAMP was detectable in parasites treated with L-phenylephrine, leaving open the question about how optimal doses of this alpha-adrenergic agonist enhance T. cruzi infectivity. Parasite responsiveness to alpha- and beta-adrenergic agonists as well as the desensitization effects define a system which regulates infectivity and could be modified at the host tissue level by naturally occurring agonists.

scholarly journals Characterization and trypanocidal activity of a β-lapachone-containing drug carrier

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0246811
Author(s):  
Juliana M. C. Barbosa ◽  
Caroline D. Nicoletti ◽  
Patrícia B. da Silva ◽  
Tatiana G. Melo ◽  
Débora O. Futuro ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Water Solubility ◽  
Drug Carrier ◽  
Chronic Phase ◽  
Therapeutic Effects ◽  
Potential Toxicity ◽  
Trypanocidal Activity ◽  
Limited Efficacy ◽  
Alternative Drugs

The treatment of Chagas disease (CD), a neglected parasitic condition caused by Trypanosoma cruzi, is still based on only two drugs, nifurtimox (Nif) and benznidazole (Bz), both of which have limited efficacy in the late chronic phase and induce severe side effects. This scenario justifies the continuous search for alternative drugs, and in this context, the natural naphthoquinone β-lapachone (β-Lap) and its derivatives have demonstrated important trypanocidal activities. Unfortunately, the decrease in trypanocidal activity in the blood, high toxicity to mammalian cells and low water solubility of β-Lap limit its systemic administration and, consequently, clinical applications. For this reason, carriers as drug delivery systems can strategically maximize the therapeutic effects of this drug, overcoming the above mentioned restrictions. Accordingly, the aim of this study is to investigate the in vitro anti-T. cruzi effects of β-Lap encapsulated in2-hydroxypropyl-β-cyclodextrin (2HP-β-CD) and its potential toxicity to mammalian cells.

scholarly journals In vitro trypanocidal activity of the Egyptian plant Schinopsis lorentizii against trypomastigote and amastigote forms of Trypanosoma cruzi

2016 ◽  
pp. 055-060 ◽  
Author(s):  
Khaled Rashed ◽  
Daniele Ferreira ◽  
Viviane Esperandim ◽  
Maria Marcal ◽  
Breno Sequeira ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Trypanocidal Activity

Synthesis, 2D-QSAR Studies and Biological Evaluation of Quinazoline Derivatives as Potent Anti-Trypanosoma cruzi Agents

2019 ◽  
Vol 15 (3) ◽  
pp. 265-276 ◽  
Author(s):  
Mariela Bollini ◽  
Ana M. Bruno ◽  
María E. Niño ◽  
Juan J. Casal ◽  
Leandro D. Sasiambarrena ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Biological Evaluation ◽  
Significant Activity ◽  
Qsar Studies ◽  
2D Qsar ◽  
Starting Point ◽  
Quinazoline Derivatives

Background: Chagas disease affects about 7 million people worldwide. Only two drugs are currently available for the treatment for this parasite disease, namely, benznidazol (Bzn) and nifurtimox (Nfx). Both drugs have limited curative power in the chronic phase of the disease. Therefore, continuous research is an urgent need so as to discover novel therapeutic alternatives. Objective: The development of safer and more efficient therapeutic anti-T. cruzi drugs continues to be a major goal in trypanocidal chemotherapy. Method: Synthesis, 2D-QSAR and drug-like physicochemical properties of a set of quinazolinone and quinazoline derivatives were studied as trypanocidal agents. All compounds were screened in vitro against Trypanosoma cruzi (Tulahuen strain, Tul 2 stock) epimastigotes and bloodstream trypomastigotes. Results: Out of 34 compounds synthesized and tested, six compounds (5a, 5b, 9b, 9h, 13f and 13p) displayed significant activity against both epimastigotes and tripomastigotes, without exerting toxicity on Vero cells. Conclusion: The antiprotozoal activity of these quinazolinone and quinazoline derivatives represents an interesting starting point for a medicinal chemistry program aiming at the development of novel chemotherapies for Chagas disease.

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