The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

scholarly journals In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

2010 ◽  
Vol 54 (8) ◽  
pp. 3318-3325 ◽  
Author(s):  
Alisson L. Matsuo ◽  
Luis S. Silva ◽  
Ana C. Torrecilhas ◽  
Bruno S. Pascoalino ◽  
Thiago C. Ramos ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Chagas Disease ◽  
Cell Invasion ◽  
Mammalian Cells ◽  
New Drugs ◽  
Drug Candidate ◽  
Acute Form ◽  
Intracellular Amastigote

ABSTRACT Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.

scholarly journals Preclinical Studies in Anti-Trypanosomatidae Drug Development

2021 ◽  
Vol 14 (7) ◽  
pp. 644
Author(s):  
Cintya Perdomo ◽  
Elena Aguilera ◽  
Ileana Corvo ◽  
Paula Faral-Tello ◽  
Elva Serna ◽  
...  
Keyword(s):  
Rural Communities ◽  
Chagas Disease ◽  
Murine Model ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Murine Macrophages ◽  
Causative Agents ◽  
Trypanosomatid Parasites

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

scholarly journals Neurotrophin Receptor TrkC Is an Entry Receptor for Trypanosoma cruzi in Neural, Glial, and Epithelial Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 4081-4087 ◽  
Author(s):  
Craig Weinkauf ◽  
Ryan Salvador ◽  
Mercio PereiraPerrin
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mammalian Cells ◽  
Chinese Hamster ◽  
Neuronal Cell ◽  
Host Cells ◽  
Neurotrophin Receptor ◽  
Content Type

ABSTRACTTrypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated byT. cruzisurfacetrans-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used byT. cruzito enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant toT. cruzibecame highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore,trkCtransfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive toT. cruziafter transfection with thetrkCgene. Additionally, NT-3 specifically blockedT. cruziinfection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blockedT. cruziinfection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected byT. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broadT. cruziinfection bothin vitroandin vivo.

scholarly journals Organometallic gold(III) [Au(Hdamp)(L14)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection

2018 ◽  
Author(s):  
Carla Duque Lopes ◽  
Ana Paula S. Gaspari ◽  
Ronaldo J. Oliveira ◽  
Ulrich Abram ◽  
José P. A. Almeida ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Hydrophobic Interactions ◽  
Covalent Bond ◽  
Acute Stage ◽  
Health Concern ◽  
Gold Compound ◽  
Docking Simulations

AbstractChagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs againstTrypanosoma cruzi, we evaluated both thein vitroandin vivoactivity of the organometallic gold(III) complex [Au(Hdamp)(L14)]Cl (L1 =SNS- donating thiosemicarbazone), which was denoted 4-Cl. Our results demonstrated that 4- Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and the intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In very-low-dosein vivoassays, 4-Cl reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage. All these changes resulted in the survival of 100% of the mice treated with 4-Cl during the acute phase. We hypothesised that 4-Cl can act directly on the parasite and may participate in the modulation of IFN-γ production at the acute stage of the disease. Molecular docking simulations showed that the compound may interact with cruzain, a thiol protease considered a possible antiparasitic drug target, primarily by hydrophobic interactions. These analyses predicted that the Cys25 residue in the cruzain binding site is approximately 3.0 Å away from the S and Au atoms of the gold compound, which could suggest formation of a possible covalent bond between cruzain and the inhibitor. Overall, we confirmed the potential of 4-Cl as a new candidate for Chagas disease treatment.

scholarly journals Chagas Disease Drug Discovery

2014 ◽  
Vol 20 (1) ◽  
pp. 22-35 ◽  
Author(s):  
Eric Chatelain
Keyword(s):  
Chagas Disease ◽  
New Technologies ◽  
Low Cost ◽  
Screening Strategy ◽  
New Drugs ◽  
In Vivo Models ◽  
The Right ◽  
The Impact

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed.

scholarly journals Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Justus Amuche Nweze ◽  
Florence N. Mbaoji ◽  
Yan-Ming Li ◽  
Li-Yan Yang ◽  
Shu-Shi Huang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Neglected Tropical Diseases ◽  
Marine Organisms ◽  
New Drugs ◽  
Screening Methods ◽  
Pharmaceutical Industries

Abstract Background Malaria and neglected communicable protozoa parasitic diseases, such as leishmaniasis, and trypanosomiasis, are among the otherwise called diseases for neglected communities, which are habitual in underprivileged populations in developing tropical and subtropical regions of Africa, Asia, and the Americas. Some of the currently available therapeutic drugs have some limitations such as toxicity and questionable efficacy and long treatment period, which have encouraged resistance. These have prompted many researchers to focus on finding new drugs that are safe, effective, and affordable from marine environments. The aim of this review was to show the diversity, structural scaffolds, in-vitro or in-vivo efficacy, and recent progress made in the discovery/isolation of marine natural products (MNPs) with potent bioactivity against malaria, leishmaniasis, and trypanosomiasis. Main text We searched PubMed and Google scholar using Boolean Operators (AND, OR, and NOT) and the combination of related terms for articles on marine natural products (MNPs) discovery published only in English language from January 2016 to June 2020. Twenty nine articles reported the isolation, identification and antiparasitic activity of the isolated compounds from marine environment. A total of 125 compounds were reported to have been isolated, out of which 45 were newly isolated compounds. These compounds were all isolated from bacteria, a fungus, sponges, algae, a bryozoan, cnidarians and soft corals. In recent years, great progress is being made on anti-malarial drug discovery from marine organisms with the isolation of these potent compounds. Comparably, some of these promising antikinetoplastid MNPs have potency better or similar to conventional drugs and could be developed as both antileishmanial and antitrypanosomal drugs. However, very few of these MNPs have a pharmaceutical destiny due to lack of the following: sustainable production of the bioactive compounds, standard efficient screening methods, knowledge of the mechanism of action, partnerships between researchers and pharmaceutical industries. Conclusions It is crystal clear that marine organisms are a rich source of antiparasitic compounds, such as alkaloids, terpenoids, peptides, polyketides, terpene, coumarins, steroids, fatty acid derivatives, and lactones. The current and future technological innovation in natural products drug discovery will bolster the drug armamentarium for malaria and neglected tropical diseases.

scholarly journals Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival

2021 ◽  
Vol 11 ◽  
Author(s):  
Cynthia Vanesa Rivero ◽  
Santiago José Martínez ◽  
Paul Novick ◽  
Juan Agustín Cueto ◽  
Betiana Nebaí Salassa ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Parasite Burden ◽  
Drug Repurposing ◽  
Parasite Load ◽  
New Drugs ◽  
Host Cells ◽  
Whole Body ◽  
Parasite Replication

T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.

Interaction of Stigmasterol with Trypanosomal Uridylyl Transferase, Farnesyl Diphosphate Synthase and Sterol 14α-demethylase: An In Silico Prediction of Mechanism of Action

2019 ◽  
Vol 16 (7) ◽  
pp. 799-807
Author(s):  
Mohammed Auwal Ibrahim ◽  
Murtala Bindawa Isah ◽  
Nasir Tajuddeen ◽  
Saadatu Auwal Hamza ◽  
Aminu Mohammed
Keyword(s):  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Binding Free Energy ◽  
Economic Loss ◽  
Farnesyl Diphosphate ◽  
New Drugs ◽  
Farnesyl Diphosphate Synthase ◽  
Highly Hydrophobic

Background: Trypanosomiasis is one of the neglected tropical diseases and continues to cause serious morbidity, mortality and economic loss. Current anti-trypanosomal drugs are antiquated and suffer from a number of serious setbacks, thereby necessitating the search for new drugs. Stigmasterol has previously demonstrated in vitro and in vivo anti-trypanosomal activity. Methods: Herein, stigmasterol was docked into three validated anti-trypanosomal drug targets; uridylyl transferase, farnesyl diphosphate synthase and sterol 14α-demethylase, in order to elucidate the possible biochemical targets for the observed anti-trypanosomal activity. Results: The binding free energy between stigmasterol and the enzymes was in the order; sterol 14α-demethylase (-8.9 kcal/mol) < uridylyl transferase (-7.9 kcal/mol) < farnesyl diphosphate synthase (-5.7 kcal/mol). At the lowest energy docked pose, stigmasterol interacts with the active site of the three trypanosomal enzymes via non-covalent interactions (apart from hydrogen bond) while highly hydrophobic stigmasterol carbon atoms (21 and 27) were crucial in the interaction with varying residues of the three anti-trypanosomal targets. Conclusion: Therefore, results from this study might suggest that stigmasterol mediated the antitrypanosomal activity through interaction with the three anti-trypanosomal targets but with more preference towards sterol 14α-demethylase.

scholarly journals Inhibition of Isoleucyl-tRNA Synthetase as a Potential Treatment for Human African Trypanosomiasis

2013 ◽  
Vol 288 (20) ◽  
pp. 14256-14263 ◽  
Author(s):  
Igor Cestari ◽  
Kenneth Stuart
Keyword(s):  
Structure Prediction ◽  
Mammalian Cells ◽  
Human African Trypanosomiasis ◽  
Competitive Inhibitor ◽  
Trna Synthetase ◽  
New Drugs ◽  
African Trypanosomiasis ◽  
Approved Drugs

Trypanosoma brucei sp. causes human African trypanosomiasis (HAT; African sleeping sickness). The parasites initially proliferate in the hemolymphatic system and then invade the central nervous system, which is lethal if not treated. New drugs are needed for HAT because the approved drugs are few, toxic, and difficult to administer, and drug resistance is spreading. We showed by RNAi knockdown that T. brucei isoleucyl-tRNA synthetase is essential for the parasites in vitro and in vivo in a mouse model of infection. By structure prediction and experimental analysis, we also identified small molecules that inhibit recombinant isoleucyl-tRNA synthetase and that are lethal to the parasites in vitro and highly selective compared with mammalian cells. One of these molecules acts as a competitive inhibitor of the enzyme and cures mice of the infection. Because members of this class of molecules are known to cross the blood-brain barrier in humans and to be tolerated, they may be attractive as leading candidates for drug development for HAT.

Prolonged in-vivo half-life of factor VIIa by fusion to albumin

2008 ◽  
Vol 99 (04) ◽  
pp. 659-667 ◽  
Author(s):  
Thomas Weimer ◽  
Wilfried Wormsbächer ◽  
Ulrich Kronthaler ◽  
Wiegand Lang ◽  
Uwe Liebing ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Half Life ◽  
Mammalian Cells ◽  
Factor Viia ◽  
Therapeutic Option ◽  
Human Albumin ◽  
Pharmacokinetic Studies ◽  
Wild Type

SummaryFor the treatment of haemophilia patients with inhibitors, recombinant factor VIIa (rFVIIa) is available as a therapeutic option to control bleeding episodes with a good balance of safety and efficacy. However, the short in-vivo half-life of approximately 2.5 hours makes multiple injections necessary, which is inconvenient for both physicians and patients. Here we describe the generation of a recombinant FVIIa molecule with an extended half-life based on genetic fusion to human albumin. The recombinant FVII albumin fusion protein (rVII-FP) was expressed in mammalian cells and upon activation displayed a FVII activity close to that of wild type FVIIa. Pharmacokinetic studies in rats demonstrated that the half-life of the activated recombinant FVII albumin fusion protein (rVIIa-FP) was extended six- to sevenfold compared with wild type rFVIIa. The in-vitro and in-vivo efficacy was evaluated and was found to be comparable to a commercially available rFVIIa (NovoSeven®). The results of this study demonstrate that it is feasible to develop a half-life extended FVIIa molecule with haemostatic properties very similar to the wild-type factor.

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