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.

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 WIPO Re:Search: Catalyzing Public-Private Partnerships to Accelerate Tropical Disease Drug Discovery and Development

2019 ◽  
Vol 4 (1) ◽  
pp. 53 ◽  
Author(s):  
Cathyryne Manner ◽  
Katy Graef ◽  
Jennifer Dent
Keyword(s):  
Drug Discovery ◽  
Intellectual Property ◽  
Neglected Tropical Diseases ◽  
Tropical Disease ◽  
New Drugs ◽  
World Intellectual Property Organization ◽  
Tropical Diseases ◽  
Middle Income ◽  
Drug Discovery And Development ◽  
Partnership Model

Tropical diseases, including malaria and a group of infections termed neglected tropical diseases (NTDs), pose enormous threats to human health and wellbeing globally. In concert with efforts to broaden access to current treatments, it is also critical to expand research and development (R&D) of new drugs that address therapeutic gaps and concerns associated with existing medications, including emergence of resistance. Limited commercial incentives, particularly compared to products for diseases prevalent in high-income countries, have hindered many pharmaceutical companies from contributing their immense product development know-how and resources to tropical disease R&D. In this article we present WIPO Re:Search, an international initiative co-led by BIO Ventures for Global Health (BVGH) and the World Intellectual Property Organization (WIPO), as an innovative and impactful public-private partnership model that promotes cross-sector intellectual property sharing and R&D to accelerate tropical disease drug discovery and development. Importantly, WIPO Re:Search also drives progress toward the United Nations Sustainable Development Goals (SDGs). Through case studies, we illustrate how WIPO Re:Search empowers high-quality tropical disease drug discovery researchers from academic/non-profit organizations and small companies (including scientists in low- and middle-income countries) to leapfrog their R&D programs by accessing pharmaceutical industry resources that may not otherwise be available to them.

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.

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.

Methods of macrophages activation and their modulation for the prospection of new antileishmania drugs: a review

2021 ◽  
Vol 37 ◽  
pp. e37077
Author(s):  
Michel Muálem de Moraes Alves ◽  
Daniel Dias Rufino Arcanjo ◽  
Rita Cássia Viana de Carvalho ◽  
Layane Valéria Amorim ◽  
Ingredy Lopes dos Santos ◽  
...  
Keyword(s):  
Immune Response ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Tropical Diseases ◽  
First Line ◽  
Phagocytic Capacity ◽  
Activity Increase ◽  
Parasitic Zoonoses ◽  
Infected Cells ◽  
Cellular Immune

Leishmaniasis are a group of parasitic zoonoses provoked by protozoa from Leishmania genus and belonging to the group of neglected tropical diseases. The search and development for new drugs is necessary not only to investigate the activity against only the parasite, but also to investigate the possible synergistic effect of new drugs with the immune response of the host. In the present review, macrophages are pointed out as potential targets of the investigation of new antileishmanial drugs, and some methodologies in order to assess their activation as response to Leishmania-infected cells are presented. Macrophages are an important role in the cellular immune response, since they are cells from mononuclear phagocytic system, the first line of defense of the host, against parasites from Leishmania genus. Phagocytic capacity, lysosomal activity, increase of nitric oxide and intracellular calcium levels are parameters regarding assessment of macrophages activation which allow them to be more hostile in order to solve the infection and lead the patient to cure. In this context, we bring 19 substances already investigated and that activate macrophages, what makes them promising in the antileishmanial treatment. Therefore, assessment of macrophages activation, are important tools for discovery of immunomodulatory compounds which have potential to act in synergism with host immune response. Such compounds might be promising as monotherapy in the treatment of leishmaniasis, as well as being used as adjuvants in vaccines and/or in combination with conventional drugs.

scholarly journals Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases

2015 ◽  
Vol 12 (104) ◽  
pp. 20141289 ◽  
Author(s):  
Kevin Williams ◽  
Elizabeth Bilsland ◽  
Andrew Sparkes ◽  
Wayne Aubrey ◽  
Michael Young ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Boolean Functions ◽  
Neglected Tropical Diseases ◽  
Quantitative Structure Activity Relationship ◽  
New Drugs ◽  
Automation System ◽  
Tropical Diseases ◽  
Standard Drug ◽  
Anti Cancer ◽  
Lead Generation

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist ‘Eve’ designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax .

Collaborations aim to develop new drugs for neglected tropical diseases

BMJ ◽  
2009 ◽  
Vol 338 (jun29 2) ◽  
pp. b2638-b2638 ◽  
Author(s):  
J. H. Tanne
Keyword(s):  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Tropical Diseases

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.

scholarly journals Seaweeds to the rescue of forgotten diseases: a review

2019 ◽  
Vol 62 (3) ◽  
pp. 211-226 ◽  
Author(s):  
Yolanda Freile-Pelegrín ◽  
Deniz Tasdemir
Keyword(s):  
Natural Products ◽  
Marine Algae ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Bioactive Molecules ◽  
Current Status ◽  
Tropical Diseases ◽  
Clinical Testing ◽  
The World ◽  
Active Substances

Abstract Neglected tropical diseases (NTDs) are a group of diseases that are predominant in the poorest parts of the world affecting 1.4 billion people. The development of new drugs is urgently needed in order to combat these forgotten diseases. Natural products from marine organisms have been widely explored as a source of new bioactive molecules. However, despite their enormous potential in drug discovery, not even one seaweed-based molecule has entered pre-clinical testing for NTDs. This review gives an overview of the current status of algal natural products against NTDs. The list of compounds is by no means exhaustive, but covers the most important classes of active substances in marine algae against the most studied NTDs.

scholarly journals Synthesis, Characterization and Antiparasitic Activity of Organometallic Derivatives of the Anthelmintic Drug Albendazole

2020 ◽  
Author(s):  
Yan Lin ◽  
Yih Ching Ong ◽  
Sarah Keller ◽  
Johannes Karges ◽  
Rafika Bouchene ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
Organometallic Compounds ◽  
Host Cells ◽  
World Health ◽  
Full Potential ◽  
Trichuris Muris ◽  
Antiparasitic Activity ◽  
Derivatives Of

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Albendazole (ABZ) is a broad‐spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with the organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths but also protozoans, namely Trichuris muris adult, Heligmosomoides polygygrus adult, Schistosoma mansoni adult, Giardia lamblia, Haemonchus contortus xL3s and Toxoplasma gondii to determine the full potential of our new compounds. Worthy of note, the ferrocene‐containing ABZ analogue 2d exhibited over 70% activity against T. muris adult in vitro and no toxicity to mammalian cells up to 100 µM. Against T. gondii, the ferrocene‐containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. However, the activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro could rather be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg/kg dose, the compounds showed moderate worm burden reductions and low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.<br>

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