Síntese e avaliação da atividade antileishmania de derivados piridínico-imidazolínicos

Abstract

Neglected Tropical Diseases (NTDs) remain a major global public health challenge, particularly leishmaniasis, whose high incidence and toxicity of current therapies demand new therapeutic alternatives. In this study, nine hybrid compounds were designed, synthesized, and evaluated through aromatic nucleophilic substitution (SNAr) reactions between pyridinic nuclei and sulfur-containing heterocycles (benzimidazole, benzoxazole, and benzothiazole). Molecular hybridization and bioisosterism strategies were applied to obtain derivatives with enhanced antiparasitic potential and improved pharmacokinetic profiles. The compounds were characterized by NMR spectroscopy (1H and 13C) and assessed for leishmanicidal activity against intracellular amastigotes of Leishmania infantum and cytotoxicity on human macrophages (THP-1). Compound 5 exhibited the best biological performance (IC₅₀ = 1.17 μM; Selectivity Index > 50), indicating high potency and low toxicity. In silico SwissADME analysis confirmed favorable lipophilicity and oral bioavailability. Overall, the molecular hybridization between pyridinic and sulfur heterocyclic cores proved to be a promising strategy for the development of new antileishmanial agents