scholarly journals Antiparasitic Effect of Stilbene and Terphenyl Compounds against Trypanosoma cruzi Parasites

2021 ◽  
Vol 14 (11) ◽  
pp. 1199
Author(s):  
Federica Bruno ◽  
Germano Castelli ◽  
Fabrizio Vitale ◽  
Simone Catanzaro ◽  
Valeria Vitale Badaco ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Flow Cytometric Analysis ◽  
New Drugs ◽  
Normal Cells ◽  
Antiparasitic Activity ◽  
Intracellular Amastigotes ◽  
Caspase 1

Background: Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago, and this drug is considered very aggressive and may cause several adverse effects. This drug currently has severe limitations, including a high frequency of undesirable side effects and limited efficacy and availability, so research to discover new drugs for the treatment of Chagas disease is imperative. Many drugs available on the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products. Methods: This study evaluated the in vitro antiparasitic activity of a series of previously synthesized stilbene and terphenyl compounds in T. cruzi epimastigotes and intracellular amastigotes. The action of the most selective compounds was investigated by flow cytometric analysis to evaluate the mechanism of cell death. The ability to induce apoptosis or caspase-1 inflammasomes was assayed in macrophages infected with T. cruzi after treatment, comparing it with that of Nifurtimox. Results: The stilbene ST18 was the most potent compound of the series. It was slightly less active than Nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase in parasites positive for Annexin V and monodansylcadaverine. Moreover, ST18 induced the activation, in infected macrophages, of caspase-1, a conserved enzyme that plays a major role in controlling parasitemia, host survival and the onset of the adaptive immune response in Trypanosoma infection. Conclusions: The antiparasitic activity of ST18 together with its ability to activate caspase-1 in infected macrophages and its low toxicity toward normal cells makes this compound interesting for further clinical investigation.

scholarly journals Antiparasitic effect of stilbene and terphenyl compounds against Trypanosoma cruzi parasites

2021 ◽  
Author(s):  
Federica Bruno ◽  
Germano Castelli ◽  
Fabrizio Vitale ◽  
Simone Catanzaro ◽  
Valeria Vitale Badaco ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Annexin V ◽  
New Drugs ◽  
Main Role ◽  
Normal Cells ◽  
Antiparasitic Activity ◽  
Intracellular Amastigotes ◽  
Caspase 1

AbstractBackgroundChagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago and is considered very aggressive and may cause several adverse effects. Currently, this drug has severe limitations, including high frequency of undesirable side effects and limited efficacy and availability and the research to discover new drugs for the treatment of Chagas disease is imperative. Many drugs available in the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products.Methodology/Principal FindingsThis study evaluated the in vitro antiparasitic activity in T. cruzi epimastigotes and intracellular amastigotes of a series of stilbene and terphenyl compounds previously synthesized. The action of the most selective compounds has been investigated by flow cytometry analysis to evaluate the mechanism of cell death. The ability to induce apoptosis or caspase-1 inflammasome were assayed in macrophages infected with T. cruzi after treatment comparing with Nifurtimox.Conclusions/SignificanceThe stilbene ST18 was the most potent compound of the series. It was slightly less active than Nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase of parasites positive to Annexin V and monodansylcadaverine. Moreover, ST18 induced the activation in infected macrophages of caspase-1, a conserved enzyme which plays a main role in controlling parasitemia, host survival, and the onset of adaptive immune response in Trypanosoma infection. The antiparasitic activity of ST18 together to its ability to activate caspase-1 in infected macrophages and its low toxicity on normal cells makes this compound interesting for further clinical investigations.Author SummaryChagas disease is a pathology caused by the protozoan parasite Trypanosoma cruzi. No progress in the treatment of this pathology has been made since benznidazole and Nifurtimox were introduced more than fifty years ago. However, these drugs have severe limitations and the research to discover new drugs for the treatment of Chagas disease is imperative. We evaluated the in vitro antiparasitic activity in T. cruzi epimastigotes of a series of stilbene and terphenyl compounds previously synthesized. The stilbene ST18 was the most potent compound of the series. It was slightly less active than nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase of parasites positive to Annexin V and monodansylcadaverine. Moreover, this compound induced the activation in infected macrophages of caspase-1, an evolutionarily conserved enzyme which plays a main role in controlling parasitemia, host survival, and the onset of adaptive immune response in T. cruzi infection. The antiparasitic activity of ST18 together to its ability to activate caspase-1 in infected macrophages and its low toxicity on normal cells makes this compound interesting for further clinical investigations.

scholarly journals SARs for the Antiparasitic Plant Metabolite Pulchrol. 3. Combinations of New Substituents in A/B-Rings and A/C-Rings

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3944
Author(s):  
Paola Terrazas ◽  
Efrain Salamanca ◽  
Marcelo Dávila ◽  
Sophie Manner ◽  
Alberto Gimenez ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Binding Sites ◽  
Hydroxyl Group ◽  
Neglected Diseases ◽  
Leishmania Braziliensis ◽  
Antiparasitic Activity ◽  
Plant Metabolite

The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.

scholarly journals Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi, the Etiological Agent of Chagas' Disease

2010 ◽  
Vol 54 (9) ◽  
pp. 3738-3745 ◽  
Author(s):  
Sharon King-Keller ◽  
Minyong Li ◽  
Alyssa Smith ◽  
Shilong Zheng ◽  
Gurpreet Kaur ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Catalytic Domain ◽  
Polypeptide Chain ◽  
Inflammatory Diseases ◽  
New Drugs ◽  
Volume Recovery ◽  
Chronic Pulmonary Diseases ◽  
Potential Inhibitors

ABSTRACT Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
New Drugs ◽  
Host Cells ◽  
Amaryllidaceae Alkaloids ◽  
Cytotoxicity Assays ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of a newly developed anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Specific Activity ◽  
New Drugs ◽  
Host Cells ◽  
Amastigote Stage ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of an anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC 50 = 3.31 μM). Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Specific Activity ◽  
New Drugs ◽  
Host Cells ◽  
Amastigote Stage ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of an anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC 50 = 3.31 μM). Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Synergic Effect of Allopurinol in Combination with Nitroheterocyclic Compounds against Trypanosoma cruzi

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Ana Lia Mazzeti ◽  
Lívia de F. Diniz ◽  
Karolina R. Gonçalves ◽  
Ruan Schott WonDollinger ◽  
Tassiane Assíria ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Load ◽  
H9c2 Cells ◽  
Cure Rate ◽  
Positive Interaction ◽  
Content Type ◽  
Intracellular Amastigotes ◽  
Subsequent Relapse

ABSTRACT Combination therapy has gained attention as a possible strategy for overcoming the limitations of the present therapeutic arsenal for Chagas disease. The aim of this study was to evaluate the effect of allopurinol in association with nitroheterocyclic compounds on infection with the Y strain of Trypanosoma cruzi. The in vitro effect of allopurinol plus benznidazole or nifurtimox on intracellular amastigotes in infected H9c2 cells was assessed in a 72-h assay. The interactions were classified as synergic for both allopurinol-nifurtimox (sums of fractional inhibitory concentrations [∑FICs] = 0.49 ± 0.08) and allopurinol-benznidazole (∑FICs = 0.48 ± 0.09). In the next step, infected Swiss mice were treated with allopurinol at 30, 60, and 90 mg/kg of body weight and with benznidazole at 25, 50, and 75 mg/kg in monotherapy and in combination at the same doses; as a reference treatment, another group of animals received benznidazole at 100 mg/kg. Allopurinol in monotherapy led to a smaller or nil effect in the reduction of parasite load and mortality rate. Treatment with benznidazole at suboptimal doses induced a transient suppression of parasitaemia with subsequent relapse in all animals treated with 25 and 50 mg/kg and in 80% of those that received 75 mg/kg. Administration of the drugs in combination significantly increased the cure rate to 60 to 100% among mice treated with benznidazole at 75 mg/kg plus 30, 60, or 90 mg/kg of allopurinol. These results show a positive interaction between allopurinol and benznidazole, and since both drugs are commercially available, their use in combination may be considered for the assessment in the treatment of Chagas disease patients.

Zinc 1,2,4-triazolo[1,5-a]pyrimidine complexes: synthesis, structural characterization and their effect against Chagas disease

2021 ◽  
Vol 17 ◽  
Author(s):  
José M. Méndez-Arriaga ◽  
Erika Rubio-Mirallas ◽  
Miguel Quirós ◽  
Manuel Sánchez-Moreno
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
New Drugs ◽  
World Health ◽  
Neglected Diseases ◽  
X Ray Diffraction ◽  
X Ray ◽  
Health Organization ◽  
The Third World

Background: The World Health Organization catalogues illnesses such as Chagas disease as neglected diseases, due the low investment in new drugs to fight them. The search for novel and non-side effects anti-parasitic compounds is one of the urgent needs of the Third World. The use of triazolopyrimidines and their metal complexes have demonstrated hopeful results in this field. Objective: This work studies the antiparasitic efficacy against Trypanosoma cruzi strains of a series of zinc triazolopyrimidine complexes. Method: A series of Zn complexes has been synthesized by the reaction between the triazolopyrimidine derivatives 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) and 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) with Zn(SO4) • 7H2O, ZnCl2, and Zn(NO3)2 • 6H2O salts. The complexes have been analyzed by spectroscopic and thermal assays and X-ray diffraction methods have been used to dilucidate the crystalline structure of one of them. The antiparasitic efficacy was tested in vitro against Trypanosoma cruzi to compare the trypanocidal effect of different ligands and counteranions to fight Chagas disease. Results: The efficacy of these compounds against Trypanosoma cruzi has also been tested to compare the influence of different ligands and counteranions on the trypanocidal effect against Chagas disease. Conclusion: Antiproliferative tests corroborate the synergistic trypanocidal effect of the triazolopyrimidine coordination complexes.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity.

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Specific Activity ◽  
New Drugs ◽  
Host Cells ◽  
Amastigote Stage ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti-T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family.Methods: the activity of each alkaloid was assessed by means of an anti-T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity.Results: we identified a single compound (hippeastrine 2) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC50 = 3.31 μM).Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Sign in / Sign up

Export Citation Format

Share Document