scholarly journals Bisphosphonate-Based Molecules as Potential New Antiparasitic Drugs

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2602 ◽  
Author(s):  
Joice Castelo Branco Santos ◽  
Jonathas Alves de Melo ◽  
Sweta Maheshwari ◽  
Wendy Marina Toscano Queiroz de Medeiros ◽  
Johny Wysllas de Freitas Oliveira ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Mevalonate Pathway ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Synthesis Process ◽  
Antiparasitic Activity ◽  
The World ◽  
Leishmania Spp ◽  
Antiparasitic Drugs ◽  
Antiparasitic Agents

Neglected tropical diseases such as Chagas disease and leishmaniasis affect millions of people around the world. Both diseases affect various parts of the globe and drugs traditionally used in therapy against these diseases have limitations, especially with regard to low efficacy and high toxicity. In this context, the class of bisphosphonate-based compounds has made significant advances regarding the chemical synthesis process as well as the pharmacological properties attributed to these compounds. Among this spectrum of pharmacological activity, bisphosphonate compounds with antiparasitic activity stand out, especially in the treatment of Chagas disease and leishmaniasis caused by Trypanosoma cruzi and Leishmania spp., respectively. Some bisphosphonate compounds can inhibit the mevalonate pathway, an essential metabolic pathway, by interfering with the synthesis of ergosterol, a sterol responsible for the growth and viability of these parasites. Therefore, this review aims to present the information about the importance of these compounds as antiparasitic agents and as potential new drugs to treat Chagas disease and leishmaniasis.

Targeting pteridine reductase 1 and dihydrofolate reductase: the old is a new trend for leishmaniasis drug discovery

2019 ◽  
Vol 11 (16) ◽  
pp. 2107-2130 ◽  
Author(s):  
Gustavo Machado das Neves ◽  
Luciano P Kagami ◽  
Itamar L Gonçalves ◽  
Vera L Eifler-Lima
Keyword(s):  
Dihydrofolate Reductase ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Molecular Targets ◽  
New Drugs ◽  
Tropical Diseases ◽  
The World ◽  
Leishmania Spp ◽  
Systemic Manifestations ◽  
Potential Drug Targets

Leishmaniasis is one of the major neglected tropical diseases in the world and it is considered endemic in 88 countries. This disease is transmitted by a Leishmania spp. infected sandfly and it may lead to cutaneous or systemic manifestations. The preconized treatment has low efficacy and there are cases of resistance to some drugs. Therefore, the search for new efficient molecular targets that can lead to the preparation of new drugs must be pursued. This review aims to evaluate both Leishmania enzymes PTR1 and DHFR-TS as potential drug targets, highlight their inhibitors and to discuss critically the use of chemoinformatics to elucidate interactions and propose new molecules against these enzymes.

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.

Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents

2021 ◽  
Vol 21 ◽  
Author(s):  
Paulo Fernando da Silva Santos-Júnior ◽  
Martine Schmitt ◽  
João Xavier de Araújo-Júnior ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Combined Therapy ◽  
Experimental Studies ◽  
New Drugs ◽  
Host Cells ◽  
Sar Studies ◽  
Promising Target ◽  
Ic50 Value ◽  
Leishmania Spp ◽  
Etiological Agents ◽  
Antiparasitic Agents

: Trypanosomatidae family belongs to the Kinetoplastida order, which consists of obligatory parasites that affect plants and all classes of vertebrates, especially humans and insects. Among the heteroxenic parasites, Leishmania spp., Trypanosoma cruzi, and T. brucei are protozoa of most significant interest for medicinal chemistry, being etiological agents of Leishmaniasis, Chagas, and Sleep Sickness diseases, respectively. Currently, inefficient pharmacotherapy, especially in chronic phases and low selectivity towards parasite/host cells, justifies the need to discover new drugs to treat them effectively. Among other targets, the sterol 14α-demethylase (CYP51), an enzyme responsible for ergosterol's biosynthesis in Trypanosomatidae parasites, has received more attention in the development of new bioactive compounds. In this context, antifungal ravuconazole proved to be the most promising drug among this class against T. cruzi, being used in combined therapy with Bnz in clinic trials. Non-antifungal inhibitors, such as VFV and VNF, have shown promising results against T. cruzi and T.brucei, respectively, being tested in Bnz-combined therapies. Among the experimental studies involving azoles, compound (15) was found to be the most promising derivative, displaying an IC50 value of 0.002 µM against amastigotes from T. cruzi, in addition to being non-toxic and highly selective towards TcCYP51 (< 25 nM). Interestingly, imidazole analog (16) was active against infectious forms of these three parasites, demonstrating Ki values of 0.17, 0.02, and 0.36 nM for CYP51 from T. cruzi, T. brucei, and L. infantum. Finally, this review will address promising inhibitors targeting sterol 14α-demethylase (CYP51) from Trypanosomatidae parasites, highlighting SAR studies, interactions with this target, and recent contributions and advances in the field, as well.

scholarly journals Susceptibility Testing of Medically Important Parasites

2017 ◽  
Vol 30 (3) ◽  
pp. 647-669 ◽  
Author(s):  
Abebe Genetu Bayih ◽  
Anjan Debnath ◽  
Edward Mitre ◽  
Christopher D. Huston ◽  
Benoît Laleu ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Neglected Tropical Diseases ◽  
State Of The Art ◽  
Life Cycles ◽  
Point Of View ◽  
New Drugs ◽  
Screening Methods ◽  
Laboratory Methods ◽  
Antiparasitic Agents

SUMMARY In the last 2 decades, renewed attention to neglected tropical diseases (NTDs) has spurred the development of antiparasitic agents, especially in light of emerging drug resistance. The need for new drugs has required in vitro screening methods using parasite culture. Furthermore, clinical laboratories sought to correlate in vitro susceptibility methods with treatment outcomes, most notably with malaria. Parasites with their various life cycles present greater complexity than bacteria, for which standardized susceptibility methods exist. This review catalogs the state-of-the-art methodologies used to evaluate the effects of drugs on key human parasites from the point of view of drug discovery as well as the need for laboratory methods that correlate with clinical outcomes.

scholarly journals Neglected tropical diseases in Brazil

2009 ◽  
Vol 51 (5) ◽  
pp. 247-253 ◽  
Author(s):  
José Angelo L. Lindoso ◽  
Ana Angélica B.P. Lindoso
Keyword(s):  
Neglected Tropical Diseases ◽  
Clinical Manifestations ◽  
Northern Region ◽  
New Drugs ◽  
World Health ◽  
Tropical Diseases ◽  
The North ◽  
The World ◽  
The Status ◽  
Health Organization

Poverty is intrinsically related to the incidence of Neglected Tropical Diseases (NTDs). The main countries that have the lowest human development indices (HDI) and the highest burdens of NTDs are located in tropical and subtropical regions of the world. Among these countries is Brazil, which is ranked 70th in HDI. Nine out of the ten NTDs established by the World Health Organization (WHO) are present in Brazil. Leishmaniasis, tuberculosis, dengue fever and leprosy are present over almost the entire Brazilian territory. More than 90% of malaria cases occur in the Northern region of the country, and lymphatic filariasis and onchocerciasis occur in outbreaks in a particular region. The North and Northeast regions of Brazil have the lowest HDIs and the highest rates of NTDs. These diseases are considered neglected because there is not important investment in projects for the development of new drugs and vaccines and existing programs to control these diseases are not sufficient. Another problem related to NTDs is co-infection with HIV, which favors the occurrence of severe clinical manifestations and therapeutic failure. In this article, we describe the status of the main NTDs currently occurring in Brazil and relate them to the HDI and poverty.

scholarly journals Bioprospecting of Nitrogenous Heterocyclic Scaffolds with Potential Action for Neglected Parasitosis: A Review

2020 ◽  
Vol 26 (33) ◽  
pp. 4112-4150
Author(s):  
Sonaly L. Albino ◽  
Jamire M. da Silva ◽  
Michelangela S. de C. Nobre ◽  
Yvnni M. S. de M. e Silva ◽  
Mirelly B. Santos ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Neglected Tropical Diseases ◽  
Poverty Rate ◽  
New Drugs ◽  
Parasitic Infections ◽  
High Poverty ◽  
Pharmacokinetic Properties ◽  
Number Of Publications ◽  
Antiparasitic Agents ◽  
High Poverty Rate

Neglected parasitic diseases are a group of infections currently considered as a worldwide concern. This fact can be attributed to the migration of these diseases to developed and developing countries, associated with therapeutic insufficiency resulted from the low investment in the research and development of new drugs. In order to overcome this situation, bioprospecting supports medicinal chemistry in the identification of new scaffolds with therapeutically appropriate physicochemical and pharmacokinetic properties. Among them, we highlight the nitrogenous heterocyclic compounds, as they are secondary metabolites of many natural products with potential biological activity. The objective of this work was to review studies within a 10-year timeframe (2009- 2019), focusing on the pharmacological application of nitrogen bioprospectives (pyrrole, pyridine, indole, quinoline, acridine, and their respective derivatives) against neglected parasitic infections (malaria, leishmania, trypanosomiases, and schistosomiasis), and their application as a template for semi-synthesis or total synthesis of potential antiparasitic agents. In our studies, it was observed that among the selected articles, there was a higher focus on the attempt to identify and obtain novel antimalarial compounds, in a way that an extensive amount of studies involving all heterocyclic nitrogen nuclei were found. On the other hand, the parasites with the lowest number of publications up until the present date have been trypanosomiasis, especially those caused by Trypanosoma cruzi, and schistosomiasis, where some heterocyclics have not even been cited in recent years. Thus, we conclude that despite the great biodiversity on the planet, little attention has been given to certain neglected tropical diseases, especially those that reach countries with a high poverty rate.

scholarly journals Systematic study of triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases.

2021 ◽  
Author(s):  
Exequiel Porta ◽  
Shane Wilkinson ◽  
María Sol Ballari ◽  
Babu Tekwani ◽  
Guillermo Labadie
Keyword(s):  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
Selectivity Index ◽  
New Drugs ◽  
Tropical Diseases ◽  
Antiparasitic Activity ◽  
Nanomolar Concentration ◽  
Stereocontrolled Synthesis ◽  
Etiological Agents ◽  
Excellent Selectivity

A series of thirty 1,2,3-triazolylsterols were prepared by a stereocontrolled synthesis and inspired by azasterols with proven antiparasitic activity. Ten of these compounds constitute chimeras/hybrids of AZA and 1,2,3-triazolyl azasterols. The entire library was assayed against the etiological agents of the parasites responsible of kinetoplastid diseases (L. donovani, T. cruzi and T. brucei). Several of the compounds were active at submicromolar/nanomolar concentration with excellent selectivity index, when compared to their activity in mammalian cells. Studies of the physicochemical properties in silico were conducted to rationalize the activities.

Natural Products: Key Prototypes to Drug Discovery Against Neglected Diseases Caused by Trypanosomatids

2020 ◽  
Vol 27 (13) ◽  
pp. 2133-2146 ◽  
Author(s):  
Marina Themoteo Varela ◽  
João Paulo S. Fernandes
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Neglected Tropical Diseases ◽  
Biological Activities ◽  
Neglected Diseases ◽  
Synthetic Compounds ◽  
Structural Variety ◽  
The World ◽  
Leishmania Spp ◽  
Per Se

Background: Neglected tropical diseases are a group of infections caused by microorganisms and viruses that affect mainly poor regions of the world. In addition, most available drugs are associated with long periods of treatment and high toxicity which limits the application and patient compliance. Investment in research and development is not seen as an attractive deal by the pharmaceutical industry since the final product must ideally be cheap, not returning the amount invested. Natural products have always been an important source for bioactive compounds and are advantageous over synthetic compounds when considering the unique structural variety and biological activities. On the other hand, isolation difficulties and low yields, environmental impact and high cost usually limit their application as drug per se. Objective: In this review, the use of natural products as prototypes for the semi-synthesis or total synthesis, as well as natural products as promising hits is covered, specifically regarding compounds with activities against trypanosomatids such as Trypanosoma spp. and Leishmania spp. Methods: Selected reports from literature with this approach were retrieved. Conclusion: As summary, it can be concluded that natural products are an underestimated source for designing novel agents against these parasites.

Signal Transduction Pathways as Therapeutic Target for Chagas Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6572-6589 ◽  
Author(s):  
Alejandra Cecilia Schoijet ◽  
Tamara Sternlieb ◽  
Guillermo Daniel Alonso
Keyword(s):  
Chagas Disease ◽  
New Technologies ◽  
Neglected Tropical Diseases ◽  
Drug Repositioning ◽  
Basic Research ◽  
Effector Proteins ◽  
Adenylyl Cyclases ◽  
Clinical Phase ◽  
Leishmania Spp ◽  
Approved Drugs

Trypanosomatids are a group of flagellated unicellular eukaryotes, causing serious human diseases including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.) and Leishmaniasis (Leishmania spp.). The second messenger cAMP is involved in numerous and fundamental processes in these parasites including differentiation between stages, proliferation, osmoregulation, oxidative stress and quorum sensing. Interestingly, its signaling pathway is quite different from that of mammals, including structurally different adenylyl cyclases, the shortage of orthologous effector proteins and the absence of G-protein-coupled-receptors, among others. These characteristics make the proteins involved in these transduction pathways good candidates for therapeutic targets. However, the identification of new unknown druggable targets involves extensive research time and is economically very expensive, making difficult the transition from basic research to the clinical phase. Trypanosomatid PDEs have characteristic binding pockets that allow for a differential inhibition from their human orthologs. Modification in the approved drugs for human to convert them into trypanocidal treatments could lead to more effective therapies, shorter lab time and lower costs. In view of the fact that kinetoplastid PDEs are highly conserved with their mammalian counterparts, and since there are already numerous drugs on the market against human PDEs, the drug repositioning approach is highly promising. The development of new technologies, higher government and industrial involvement and more scientists committed to basic investigation, are the key to ultimately find an effective treatment and cure for the neglected tropical diseases.

scholarly journals Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 187 ◽  
Author(s):  
María Álvarez-Bardón ◽  
Yolanda Pérez-Pertejo ◽  
César Ordóñez ◽  
Daniel Sepúlveda-Crespo ◽  
Nestor M. Carballeira ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput Screening ◽  
High Performance ◽  
Social Issues ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
World Health ◽  
World Population ◽  
The World ◽  
Health Organization

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum, is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.

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