Aplicação de biomassa nordestina no desenvolvimento de novos produtos/processos e controle de leishmaniose

Abstract

Cutaneous leishmaniasis (CL) is a neglected tropical disease that affects vulnerable populations and is currently treated with highly toxic drugs. This thesis investigated the pharmacological potential of the major constituents of cashew nut shell liquid (CNSL) — anacardic acid (AA), cardol (CD), and cardanol (CDN)—isolated by acid-base extraction and chromatography, as well as their formulations with silver nanoparticles (AgNPs), resulting in the AgAA and AgCD complexes. The aim was to develop safer and more selective alternative or adjuvant therapies for the treatment of CL. AA, CD, and CDN were extracted and purified, followed by nanoparticle synthesis via microwave irradiation. In vitro assays were conducted to evaluate cytotoxicity in macrophages, antileishmanial activity against promastigote and amastigote forms of Leishmania braziliensis, and the selectivity index (SI). Subsequently, the compounds were tested in vivo in zebrafish for acute toxicity and central nervous system effects, through behavioral assays and molecular docking with the GABAA receptor. Finally, the most promising compounds, CD and AgCD, were tested in Balb/C mice experimentally infected with L. braziliensis in the right hind paw. Edema progression, parasite load, and the pro- and anti-inflammatory cytokine profile were analyzed. CD showed strong antileishmanial activity (IC50 = 4.8 μg·mL−1), but high cytotoxicity (CC50 = 13.5 μg·mL−1), whereas AgCD demonstrated lower cytotoxicity (CC50 = 195.0 μg·mL−1), higher selectivity (SI = 16.9), and maintained efficacy against the parasite. AA displayed low selectivity and limited efficacy, even after silver functionalization. Zebrafish assays showed that CD significantly affected locomotion and light/dark preference, which was associated with its high affinity for the GABAA receptor, confirmed by molecular docking. In the murine model, CD eliminated parasites but caused alopecia, cachexia, and lethargy. AgCD-treated groups exhibited a slower therapeutic response but with lower toxicity and effective parasite load control, making it a promising candidate for alternative therapy of cutaneous leishmaniasis, especially in cases where pharmacological safety is a priority.