OPTIMIZATION OF A GC-MS METHOD FOR STEROL PROFILING IN Leishmania spp. AND EVALUATION OF IMIDAZO[1,2-α] PYRAZINE DERIVATIVES
Leishmaniasis. Ergosterol. Apoptosis. imidazo[1,2-α] pyrazine. Medicinal chemistry
Leishmaniasis represents a major global public health problem, predominantly affecting tropical and subtropical regions, with an estimated incidence of 1 million new cases annually. This epidemiological scenario is further aggravated by factors such as global warming, globalization, and intense human migration, all of which directly influence the geographical distribution of both vectors and parasites. Currently, conventional chemotherapy presents severe limitations, including high toxicity, variable efficacy, and the emergence of drug-resistant parasites, thereby encouraging the search for new therapeutic targets, such as the sterol biosynthesis pathway. This work was divided into two parts. Initially, a protocol was optimized for the characterization of sterol profiles in Leishmania major and Leishmania infantum using Gas Chromatography coupled to Mass Spectrometry (GC-MS), allowing the identification of the major sterols of these species under conditions that mimic pharmacological treatment and host systemic stress. The second stage of the project consists of evaluating novel imidazo[1,2-α] pyrazine derivatives, developed and optimized in recent years through medicinal chemistry design strategies. These compounds primarily target the Leishmania Casein Kinase 1 enzyme (L-CK1.2), a multifunctional protein associated with the inhibition of apoptosis in host macrophages, cytoskeletal organization, and regulation of ergosterol biosynthesis. In this subsequent phase, the effects of these derivatives on cell death and infection mechanisms will be investigated, together with the ultrastructural characterization of the parasite and the evaluation of the direct involvement of these compounds in the modulation of the sterol biosynthesis pathway.