Exploring novel Se-compounds as promising therapeutical option for leishmaniasis management

Abstract

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.