Recent Advances in Treatment and Diagnosis of Leishmaniasis, Trypanosomiasis and Other Neglected Tropical Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 9866

Special Issue Editor

Hellenic Pasteur Institute, Athens, Greece
Interests: NTDs; leishmaniases and trypanosomiases; antiparasitic drug discovery; epidemiology; target identification and validation; targeted therapy

Special Issue Information

Dear colleagues,

Neglected tropical diseases (NTDs) are caused by a variety of viral, bacterial, and parasitic pathogens. The diseases are called neglected because of the big contrast with the four infectious diseases—AIDS, tuberculosis, malaria, and recently COVID-19-, which receive greater treatment and research funding. This big contrast remains today, despite the fact that the World Health Organization estimates that more than one billion people—approximately one-sixth of the world’s population—suffer from at least one NTD. The aim of this Special Issue is the publication of original research articles, reviews, and case reports in order to shed light on NTD diagnosis and drug discovery efforts aiming to circumvent limitations of current chemotherapy. With respect to drug discovery efforts, the Special Issue will focus on complementary approaches such as molecular target identification and validation, efficacy of new compounds and potential leads, mechanisms of action, docking studies, and others. The second objective focuses on innovative approaches for diagnosis, epidemiological data showing the recent trends of disease burden, and recent advances that contribute to disease surveillance and to examination of the pathogen genetic background associated with virulence, clinical outcome, and drug resistance.

Dr. Despina Smirlis
Guest Editor

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Keywords

  • neglected diseases
  • leishmaniasis
  • trypanosomiasis
  • drug efficacy
  • target identification and validation
  • therapy
  • diagnosis
  • mechanisms of action
  • diagnosis
  • epidemiology

Published Papers (4 papers)

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Research

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21 pages, 1177 KiB  
Article
Evaluation of the Anti-Leishmania mexicana and -Trypanosoma brucei Activity and Mode of Action of 4,4′-(Arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
by Olalla Barreiro-Costa, Cristina Quiroga Lozano, Erika Muñoz, Patricio Rojas-Silva, Andrea Medeiros, Marcelo A. Comini and Jorge Heredia-Moya
Biomedicines 2022, 10(8), 1913; https://doi.org/10.3390/biomedicines10081913 - 07 Aug 2022
Cited by 1 | Viewed by 1631
Abstract
Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were [...] Read more.
Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC50 ≤ 10 µM against the promastigote and the bloodstream stage of Leishmania mexicana and Trypanosoma brucei brucei, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards L. mexicana and T. brucei (selectivity index, SI, compared to murine macrophages = 5–26). The exception was one derivative displaying an SI (>111–189) against T. brucei that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13–28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective T. brucei. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity. Full article
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27 pages, 9345 KiB  
Article
Naphthoquinone as a New Chemical Scaffold for Leishmanicidal Inhibitors of Leishmania GSK-3
by Victor Sebastián-Pérez, Paula Martínez de Iturrate, Montserrat Nácher-Vázquez, Luis Nóvoa, Concepción Pérez, Nuria E. Campillo, Carmen Gil and Luis Rivas
Biomedicines 2022, 10(5), 1136; https://doi.org/10.3390/biomedicines10051136 - 14 May 2022
Cited by 4 | Viewed by 2150
Abstract
More than 1 billion people live in areas endemic for leishmaniasis, which is a relevant threat for public health worldwide. Due to the inadequate treatments, there is an urgent need to develop novel alternative drugs and to validate new targets to fight this [...] Read more.
More than 1 billion people live in areas endemic for leishmaniasis, which is a relevant threat for public health worldwide. Due to the inadequate treatments, there is an urgent need to develop novel alternative drugs and to validate new targets to fight this disease. One appealing approach is the selective inhibition of protein kinases (PKs), enzymes involved in a wide range of processes along the life cycle of Leishmania. Several PKs, including glycogen synthase kinase 3 (GSK-3), have been validated as essential for this parasite by genetic or pharmacological methods. Recently, novel chemical scaffolds have been uncovered as Leishmania GSK-3 inhibitors with antiparasitic activity. In order to find new inhibitors of this enzyme, a virtual screening of our in-house chemical library was carried out on the structure of the Leishmania GSK-3. The virtual hits identified were experimentally assayed both for leishmanicidal activity and for in vitro inhibition of the enzyme. The best hits have a quinone scaffold. Their optimization through a medicinal chemistry approach led to a set of new compounds, provided a frame to establish biochemical and antiparasitic structure–activity relationships, and delivered molecules with an improved selectivity index. Altogether, this study paves the way for a systemic search of this class of inhibitors for further development as potential leishmanicidal drugs. Full article
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17 pages, 9777 KiB  
Article
In Vivo Efficacy of SQ109 against Leishmania donovani, Trypanosoma spp. and Toxoplasma gondii and In Vitro Activity of SQ109 Metabolites
by Kyung-Hwa Baek, Trong-Nhat Phan, Satish R. Malwal, Hyeryon Lee, Zhu-Hong Li, Silvia N. J. Moreno, Eric Oldfield and Joo Hwan No
Biomedicines 2022, 10(3), 670; https://doi.org/10.3390/biomedicines10030670 - 14 Mar 2022
Cited by 5 | Viewed by 3055
Abstract
SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has [...] Read more.
SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of Leishmania, Trypanosoma spp. as well as Toxoplasma infection. In the T. cruzi mouse model, 80% of SQ109-treated mice survived at 40 days post-infection. Even though SQ109 did not cure all mice, these results are of interest since they provide a basis for future testing of combination therapies with the azole posaconazole, which acts synergistically with SQ109 in vitro. We also found that SQ109 inhibited the growth of Toxoplasma gondii in vitro with an IC50 of 1.82 µM and there was an 80% survival in mice treated with SQ109, whereas all untreated animals died 10 days post-infection. Results with Trypanosoma brucei and Leishmania donovani infected mice were not promising with only moderate efficacy. Since SQ109 is known to be extensively metabolized in animals, we investigated the activity in vitro of SQ109 metabolites. Among 16 metabolites, six mono-oxygenated forms were found active across the tested protozoan parasites, and there was a ~6× average decrease in activity of the metabolites as compared to SQ109 which is smaller than the ~25× found with mycobacteria. Full article
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Review

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16 pages, 1289 KiB  
Review
Potential of Triterpenic Natural Compound Betulinic Acid for Neglected Tropical Diseases New Treatments
by Vinícius Rocha, Helenita Quadros, Cássio Meira, Laís Silva, Dahara Carvalho, Katharine Hodel, Diogo Moreira and Milena Soares
Biomedicines 2022, 10(4), 831; https://doi.org/10.3390/biomedicines10040831 - 01 Apr 2022
Cited by 7 | Viewed by 2208
Abstract
Neglected tropical diseases are one of the most important public health problems in many countries around the world. Among them are leishmaniasis, Chagas disease, and malaria, which contribute to more than 250 million infections worldwide. There is no validated vaccine to prevent these [...] Read more.
Neglected tropical diseases are one of the most important public health problems in many countries around the world. Among them are leishmaniasis, Chagas disease, and malaria, which contribute to more than 250 million infections worldwide. There is no validated vaccine to prevent these infections and the treatments available are obsolete, highly toxic, and non-effective due to parasitic drug resistance. Additionally, there is a high incidence of these diseases, and they may require hospitalization, which is expensive to the public health systems. Therefore, there is an urgent need to develop new treatments to improve the management of infected people, control the spread of resistant strains, and reduce health costs. Betulinic acid (BA) is a triterpene natural product which has shown antiparasitic activity against Leishmania, Trypanosoma cruzi, and Plasmodium. Here, we review the main results regarding the in vitro and in vivo pharmacological activity of BA and its derivatives against these parasites. Some chemical modifications of BA have been shown to improve its activities against the parasites. Further improvement on studies of drug-derived, as well as structure–activity relationship, are necessary for the development of new betulinic acid-based treatments. Full article
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