DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF INDOLE-BASED COMPOUNDS AGAINST LEISHMANIASIS

Leishmaniasis is a neglected tropical disease produced by Leishmania protozoan parasites, transmitted by the bite of infected female sandflies. The disease infects more than 12 million people worldwide and threatens additional hundreds of millions of people, primarily in the tropics and subtropics. Leishmaniasis manifests in a variety of clinical forms, ranging from self-healing cutaneous leishmaniasis to the fatal visceral form if untreated. Despite decades of use, current chemotherapy is limited to a few drugs such as pentavalent antimonials, amphotericin B, miltefosine, and paromomycin. However, these drugs typically have serious drawbacks such as relevant side effects, high costs, long treatment duration, and, most importantly, an increasing prevalence of drug-resistant strains. Thus, the search for new, effective, and safe therapeutic agents is an urgent need. Among the many chemical scaffolds that have been screened for antiparasitic activity, indole derivatives are worth noting for their rich spectrum of biological activities and ability to bind to many biological targets. Over the last decade, several studies have reported the promising activity of indole-based molecules against different Leishmania species. Natural indole alkaloids, as well as synthetic derivatives such as bisindoles, indole-imidazoles, and others, have demonstrated potent antileishmanial effects both in vitro and in vivo. Therefore, the design and synthesis of new indole-derived compounds is a rational and attractive option in the search for new antileishmanial drugs. In this context, the present thesis aims at identifying new antileishmanial compounds by designing, synthesising, and biologically investigating three groups of indole-based analogues: indole-imidazole hybrids, bisindoles, and indole isoindolinones. Different indole-imidazoles have been synthesised following a previously reported procedure in the literature. However, this route presents limitations in the variability of imidazole substituents. In order to improve this limitation, two other synthetic routes were investigated. The first one, based on the Van Leusen reaction, resulted in a single analogue due to insurmountable limitations of the methodology. A new optimised procedure involving the alkylation of preformed imidazoles with 3-(2-iodoethyl)-1H-indole allowed the synthesis of new derivatives, increasing the covered chemical space. Four different families of bisindoles have been synthesised to evaluate their biological activity against leishmaniasis. These families are: amines, amides, esters, and carboxylic acids. The introduction of glycosylated substituents has been performed in order to improve pharmacokinetics and activity. The chemistry of indole-isoindolinone derivatives has been studied, allowing synthesising three different families of compounds: di-substituted, imines and di-substituted alkoxy derivatives.