5 research outputs found
Small molecules containing chalcogen elements (S, Se, Te) as new warhead to fight neglected tropical diseases
Neglected tropical diseases (NTDs) encompass a group of infectious diseases with a protozoan etiology, high
incidence, and prevalence in developing countries. As a result, economic factors constitute one of the main
obstacles to their management. Endemic countries have high levels of poverty, deprivation and marginalization
which affect patients and limit their access to proper medical care. As a matter of fact, statistics remain un-
collected in some affected areas due to non-reporting cases. World Health Organization and other organizations
proposed a plan for the eradication and control of the vector, although many of these plans were halted by the
COVID-19 pandemic. Despite of the available drugs to treat these pathologies, it exists a lack of effectiveness
against several parasite strains. Treatment protocols for diseases such as American trypanosomiasis (Chagas
disease), leishmaniasis, and human African trypanosomiasis (HAT) have not achieved the desired results. Un-
fortunately, these drugs present limitations such as side effects, toxicity, teratogenicity, renal, and hepatic
impairment, as well as high costs that have hindered the control and eradication of these diseases. This review
focuses on the analysis of a collection of scientific shreds of evidence with the aim of identifying novel chalcogen-
derived molecules with biological activity against Chagas disease, leishmaniasis and HAT. Compounds illustrated
in each figure share the distinction of containing at least one chalcogen element. Sulfur (S), selenium (Se), and
tellurium (Te) have been grouped and analyzed in accordance with their design strategy, chemical synthesis
process and biological activity. After an exhaustive revision of the related literature on S, Se, and Te compounds,
183 compounds presenting excellent biological performance were gathered against the different causative agents
of CD, leishmaniasis and HAT
Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity
Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies
Exploring novel Se-compounds as promising therapeutical option for leishmaniasis management
Globally, more than one billion people are affected by neglected tropical diseases (NTDs). The
control, treatment, and elimination of NTDs, which mainly affect socio-economically disadvantaged
regions, is one of the crucial obstacles for these countries to achieve health equity1
.
Leishmaniasis is a NTD and the second leading cause of death from parasites in the world. Between
700,000 and 1 million new cases are reported worldwide each year. Treatment remains a challenge
and still relies on compounds with toxic side effects. More than 20 parasite species cause
leishmaniasis, making difficult the use of the same treatment regimens in multiple regions. There is
no universal treatment for leishmaniasis2,3
. For many decades, most patients have been treated with
intravenous or intramuscular injections of antimonials as first-line treatment. The use of antimonials
is associated with life-threatening side effects, including damage to the heart, liver, and pancreas. In
addition, treatments vary between regions and depend on the form of leishmaniasis, the causative
parasite, the immune status of the patient and the local availability of therapy. Therefore, new
treatments for leishmaniasis are urgently needed4
.
Selenium (Se) is a metalloid of the chalcogen group. Se is among the essential trace elements
because of its key role in cellular and thyroid metabolism, fertility, immune function, protection against
oxidative damage and other vital functions5
. Se is acquired through the diet in two main forms:
selenocysteine, found mostly in animal foods, and selenomethionine, found in plant products. Dietary
Se-compounds differ in their metabolism and ability to produce different metabolites. The biological
activity of Se-compounds is exerted via their metabolites. Therefore, the routes by which each
compound is metabolized, and the relative abundance of each metabolite are related to their efficacy
in the prevention and treatment of different diseases6
. Se plays a key role in the immune response
against leishmaniasis, a disease caused by the Leishmania parasite7
. Low Se levels are associated
with more severe forms of the disease, due to reduced antioxidant enzyme activity and increased
oxidative stress. This suggests that Se is important in the pathophysiology of leishmaniasis, and its
deficiency may aggravate Leishmania infection8
.
The scientific literature is not abundant in relation to the development of new organic compounds
derived from Se for the treatment of leishmaniasis. Studies have shown the antioxidant, antiviral, and
anticancer properties of Se, it has been incorporated into antimicrobial nanomaterials for the
treatment of Leishmania strains, with promising results, so it can be considered as an attractive novel
therapeutic agent.
As a consequence of the problems shown by drugs for the treatment of leishmaniasis, research into
newly synthesized compounds that improve these limitations is necessary. For this reason, the aim
of this Memory entitled: "Exploring novel se-compounds as promising therapeutical option for
leishmaniasis management", is to provide an advance in the knowledge of a type of structures that
can contribute as promising therapeutic agents for this disease. Our research group has more than
10 years of experience in the synthesis and biological evaluation of new synthesized Se-derivatives,
which presented superior levels of activity and selectivity than reference drugs currently used in clinic.
The chemical compounds presented in this Ph.D. project are newly synthesized and have been
developed by means of a rational design and starting from economically accessible reagents. The
structure of these compounds is characterized by their simplicity, being compounds mostly of low
molecular weight, with molecular symmetry, and the presence of at least one Se atom in different
functional groups. In some cases, the sulfur (S) analog has been synthesized, with the aim of
evaluating the importance of the Se atom in the biological activity of the compounds. The results
obtained during the development of this research project were grouped into Chapters I, II, and III
Small molecules containing chalcogen elements (S, Se, Te) as new warhead to fight neglected tropical diseases
Neglected tropical diseases (NTDs) encompass a group of infectious diseases with a protozoan etiology, high
incidence, and prevalence in developing countries. As a result, economic factors constitute one of the main
obstacles to their management. Endemic countries have high levels of poverty, deprivation and marginalization
which affect patients and limit their access to proper medical care. As a matter of fact, statistics remain un-
collected in some affected areas due to non-reporting cases. World Health Organization and other organizations
proposed a plan for the eradication and control of the vector, although many of these plans were halted by the
COVID-19 pandemic. Despite of the available drugs to treat these pathologies, it exists a lack of effectiveness
against several parasite strains. Treatment protocols for diseases such as American trypanosomiasis (Chagas
disease), leishmaniasis, and human African trypanosomiasis (HAT) have not achieved the desired results. Un-
fortunately, these drugs present limitations such as side effects, toxicity, teratogenicity, renal, and hepatic
impairment, as well as high costs that have hindered the control and eradication of these diseases. This review
focuses on the analysis of a collection of scientific shreds of evidence with the aim of identifying novel chalcogen-
derived molecules with biological activity against Chagas disease, leishmaniasis and HAT. Compounds illustrated
in each figure share the distinction of containing at least one chalcogen element. Sulfur (S), selenium (Se), and
tellurium (Te) have been grouped and analyzed in accordance with their design strategy, chemical synthesis
process and biological activity. After an exhaustive revision of the related literature on S, Se, and Te compounds,
183 compounds presenting excellent biological performance were gathered against the different causative agents
of CD, leishmaniasis and HAT
Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity
Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies