Heterocyclic N-oxides - A Promising Class of Agents against Tuberculosis, Malaria and Neglected Tropical Diseases

Heterocyclic N-oxides have emerged as promising agents against a number of diseases and disorders, especially infectious diseases. This review analyzes the emergence and development of this scaffold in the medicinal chemistry, focusing mainly on the discovery of new heterocyclic N-oxide compounds with potent activity against tuberculosis, malaria and neglected tropical diseases (i.e. leishmaniasis and Chagas disease). A number of heterocyclic N-oxides are described herein, nevertheless, the following chemical classes deserve to be highlighted due to a large number of reports in the literature about their promising pharmacological effects: furoxan, benzofuroxan, quinoxaline 1,4-di-N-oxide, indolone N-oxide and benzimidazole N-oxide. In order to describe those most promising compounds, we included in this review only those most biologically active heterocyclic Noxide published since 2000.

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Genomic and phenotypic characterization of experimentally selected resistant Leishmania donovani reveals a role for dynamin-1 like protein in the mechanism of resistance to a novel anti-leishmanial compound

10.1101/2021.01.05.425522 ◽

2021 ◽

Author(s):

Aya Hefnawy ◽

Gabriel Negreira ◽

Marlene Jara ◽

James A. Cotton ◽

Ilse Maes ◽

...

Keyword(s):

Drug Resistance ◽

Visceral Leishmaniasis ◽

Infectious Diseases ◽

Leishmania Donovani ◽

Neglected Tropical Diseases ◽

Arms Race ◽

Etiological Agent ◽

Phenotypic Characterization ◽

Tropical Diseases

AbstractThe implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common practice for many infectious diseases, but not for Neglected Tropical Diseases. Here, we explored and demonstrated the importance of this approach, using as paradigms Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross resistance to these drugs, suggesting a new and unique mechanism. By whole genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-related proteins, a group of proteins that impacts the shapes of biological membranes by mediating fusion and fission events, with a putative role in mitochondrial fission. We found that L. donovani lines genetically engineered to harbor the two identified LdoDLP1 mutations were resistant to TCMDC-143345 and displayed altered mitochondrial properties. By homology modeling, we showed how the two LdoDLP1 mutations may influence protein structure and function. Taken together, our data reveal a clear involvement of LdoDLP1 in the adaptation/resistance of L. donovani to TCMDC-143345.ImportanceHumans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively, once it has already been established in clinical settings. We previously recommended to keep one step ahead in the host-pathogen arms race and implement prospective DR studies in the R&D pipeline, a common practice for many infectious diseases, but not for NTDs. Here, using Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL, as paradigms, we experimentally selected resistance to the compound and proceeded to genomic and phenotypic characterization of DR parasites. The results gathered in the present study suggest a new DR mechanism involving the L. donovani dynamin-1 like protein (LdoDLP1) and demonstrate the practical relevance of prospective DR studies.

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How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

Expert Opinion on Drug Discovery ◽

10.1080/17460441.2019.1646723 ◽

2019 ◽

Vol 14 (11) ◽

pp. 1103-1112 ◽

Cited By ~ 4

Author(s):

Andreas H. Laustsen

Keyword(s):

Monoclonal Antibodies ◽

Infectious Diseases ◽

Neglected Tropical Diseases ◽

Tropical Diseases

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Schistosomiasis, strongyloidiasis and Chagas disease: the leading imported neglected tropical diseases in Italy

Journal of Travel Medicine ◽

10.1093/jtm/taz100 ◽

2019 ◽

Vol 27 (1) ◽

Cited By ~ 3

Author(s):

Lorenzo Zammarchi ◽

Federico Gobbi ◽

Andrea Angheben ◽

Michele Spinicci ◽

Dora Buonfrate ◽

...

Keyword(s):

Chagas Disease ◽

Neglected Tropical Diseases ◽

Agar Plate ◽

Strongyloides Stercoralis ◽

Stool Culture ◽

Diagnostic Tools ◽

Tropical Diseases ◽

Foreign Born ◽

National Policies ◽

And Control

Abstract Background In recent years, an increasing number of individuals affected by neglected tropical diseases (NTDs) have been observed in Italy, due to migration, international travels and climate changes. Reliable data on the current NTD epidemiology in Italy and the health system preparedness on this issue are not available. Methods We report the results of a survey on selected NTDs (schistosomiasis, strongyloidiasis, echinococcosis, Chagas disease, leishmaniasis, cysticercosis, filariasis and scabies) in nine Italian sentinel centres, in order to investigate their occurrence throughout the country and identify which ones are a priority for public health interventions, development of protocols for case management, and training activities. To explore the preparedness of the centres, we investigate the availability of specific diagnostic tools and drugs, needed for the management of the most common NTDs. We also reviewed and summarized the available national policies, recommendations and guidelines on NTDs in Italy. Results Overall, 4123 NTDs cases were diagnosed in nine Italian centres within a 7-year period (2011–2017). Schistosomiasis and strongyloidiasis were the most common NTDs, accounting for about one-third each of all the diagnosed cases, followed by Chagas disease. The number of cases showed a significant trend to increase over time, mainly due to foreign-born subjects. Serology for Schistosoma spp. and Strongyloides stercoralis was available in seven and five centres, respectively. Agar plate stool culture for S. stercoralis was available in three sites. Ivermectin and praziquantel were always available in six centres. Six national policies, recommendations and guidelines documents were available, but for the most part, they are not fully implemented yet. Conclusions This survey showed how some NTDs, such as schistosomiasis and strongyloidiasis, are becoming more common in Italy, due to multiple components. A list of seven key actions was proposed, in order to improve diagnosis, management and control of NTDs in Italy.

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Community Based Chagas Control Program

Archives of Infectious Diseases & Therapy ◽

10.33140/aidt.02.02.06 ◽

2018 ◽

Vol 2 (2) ◽

Keyword(s):

Chagas Disease ◽

Neglected Tropical Diseases ◽

Control Program ◽

Poor Quality ◽

World Health ◽

Tropical Diseases ◽

Social Instability ◽

Main Determinants ◽

Health Organization ◽

Effective Transmission

In 2012, World Health Organization published the first ever Neglected Tropical Diseases (NTD) Roadmap, entitled “Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases: A Roadmap for Implementation.” This report brought international attention to Chagas and other NTDs and provided a framework to guide implementation of policies and strategies set out in the Global Plan to Combat Neglected Tropical Diseases 2008-2015. Chagas disease, endemic to Bolivia, is considered the third most common parasitic disease globally, after malaria and schistosomiasis. It is estimated that six to seven million persons are infected worldwide. [1] Bolivia has the highest rate of endemic Chagas disease in the Americas. Chagas disease is both a disease of poverty and, like other neglected tropical diseases, poverty promoting. [2] Chagas disease is associated with multiple social and environmental determinants in communities marked by poverty. Salient among the main determinants are poor-quality dwellings, social instability, the combined presence of certain environmental factors, such as the Chagas vectors, mammals that serve as reservoirs of the disease and human exposure, creating the conditions for perpetuating the effective transmission of the infection and its endemicity. These challenges put pregnant women, young children and children with disabilities at especially high risk for contracting Chagas disease. Left untreated, Chagas disease can lead to serious heart, digestive and neurological conditions.

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COVID-19 epidemic in the US—A gateway to screen for tuberculosis, HIV, viral hepatitides, Chagas disease, and other neglected tropical diseases among Hispanics

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008953 ◽

2020 ◽

Vol 14 (12) ◽

pp. e0008953

Author(s):

Jonathan Schultz ◽

Peter Hyson ◽

Daniel B. Chastain ◽

Amal A. Gharamti ◽

Carlos Franco-Paredes ◽

...

Keyword(s):

Chagas Disease ◽

Neglected Tropical Diseases ◽

Tropical Diseases ◽

The Us

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An Overview on the Therapeutics of Neglected Infectious Diseases—Leishmaniasis and Chagas Diseases

Frontiers in Chemistry ◽

10.3389/fchem.2021.622286 ◽

2021 ◽

Vol 9 ◽

Author(s):

Brindha J ◽

Balamurali M. M ◽

Kaushik Chanda

Keyword(s):

Infectious Diseases ◽

Chagas Disease ◽

Biosynthetic Pathway ◽

Neglected Tropical Diseases ◽

Nucleoside Analogs ◽

Severe Toxicity ◽

Drug Candidates ◽

Chemical Structures ◽

The Past ◽

Associated Proteins

Neglected tropical diseases (NTDs) as termed by WHO include twenty different infectious diseases that are caused by bacteria, viruses, and parasites. Among these NTDs, Chagas disease and leishmaniasis are reported to cause high mortality in humans and are further associated with the limitations of existing drugs like severe toxicity and drug resistance. The above hitches have rendered researchers to focus on developing alternatives and novel therapeutics for the treatment of these diseases. In the past decade, several target-based drugs have emerged, which focus on specific biochemical pathways of the causative parasites. For leishmaniasis, the targets such as nucleoside analogs, inhibitors targeting nucleoside phosphate kinases of the parasite’s purine salvage pathway, 20S proteasome of Leishmania, mitochondria, and the associated proteins are reviewed along with the chemical structures of potential drug candidates. Similarly, in case of therapeutics for Chagas disease, several target-based drug candidates targeting sterol biosynthetic pathway (C14-ademethylase), L-cysteine protease, heme peroxidation, mitochondria, farnesyl pyrophosphate, etc., which are vital and unique to the causative parasite are discussed. Moreover, the use of nano-based formulations towards the therapeutics of the above diseases is also discussed.

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Neglected infectious diseases in the geriatrics

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20214862 ◽

2021 ◽

Author(s):

Abrar Abdulfattah Al Yamani ◽

Yahya Mohammad Falqi ◽

Yussif Mohammed Alnawar ◽

Lama Mohammed Almahrous ◽

Haitham Ahmed Alwael ◽

...

Keyword(s):

Infectious Diseases ◽

Elderly Population ◽

Neglected Tropical Diseases ◽

Dengue Infection ◽

The Elderly ◽

Current Evidence ◽

Severe Dengue ◽

Tropical Diseases ◽

Life Years ◽

Populations At Risk

Infectious diseases in the elderly population pose a significant threat to their lives. Neglected tropical diseases significantly impact the health of the affected patients and populations at risk. Reports show that many of these disorders are among the highest ten most typical causes of disability-adjusted life years. In the present literature review, we have discussed the most common neglected tropical infections in geriatrics based on data from the current studies in the literature. Different infections can affect the geriatric population. However, evidence shows that this population is susceptible to developing severe disease-related conditions. This has been reported with dengue infection, onchocerciasis, and cholera. It has been demonstrated that ocular lesions and other clinical manifestations are highest among the elderly population with onchocerciasis. Severe dengue and dengue hemorrhagic fever are also reported at a high rate in this age group. Concurrent infections and disorders were documented with many of these infections, probably due to reduced immunity. Socioeconomic factors, co-morbidities, access to healthcare settings, environmental factors, sanitation, clustering, and overcrowding contribute to the frequency of neglected tropical diseases in the elderly. Further studies are still needed because the current report is scarce, which might underestimate the current evidence.

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