Investigação de uma classe de arilmorfolinas contra a doença de chagas e leishmaniose: planejamento molecular, síntese e avaliação biológica in vitro

Abstract

In this work, the biological activity of 25 compounds from the arylmorpholine class was investigated against the amastigote forms of the parasites Trypanosoma cruzi (T. cruzi) and Leishmania infantum (L. infantum), responsible for Chagas disease and visceral leishmaniasis, respectively. These compounds were obtained through a simple synthetic route, starting with a Nucleophilic Aromatic Substitution reaction, followed by catalytic hydrogenation of the nitro group, and finalized with an amidation reaction, and they were characterized by ¹H and ¹³C APT NMR spectroscopy. Hit 1 showed high potency against T. cruzi (IC₅₀ 0.76 µM and SI = 109.5) and moderate against L. infantum (IC₅₀ 10.7 µM and SI 36.3). However, some limitations were identified in its in vitro pharmacokinetic profile, such as low kinetic solubility, high metabolic instability, and low gastrointestinal permeability, all attributed to the compound's high lipophilicity. Therefore, based on structure–activity relationship (SAR) analysis, structural modifications were made to the benzoyl, central aryl, and morpholine fragments to overcome these limitations, through the evaluation of the theoretical clogP values. The investigation included the removal of methoxy groups, the introduction of an endocyclic nitrogen into the aromatic rings, the removal of the morpholine moiety, and the replacement of the trifluoromethyl (CF₃) group with other substituents. The most promising derivative against T. cruzi in the benzoyl fragment was compound 10 (IC₅₀ 2.1 µM and clogP 2.26), featuring an endocyclic nitrogen at the ortho position and a hydroxyl group at the para position. For the central aryl fragment, the most active compound was derivative 21 (IC₅₀ < 4.3 µM and clogP = 2.66), bearing a fluorine atom directly attached to the aromatic ring. Against L. infantum, two derivatives showed equivalent activities to hit 1, compound 9 (IC₅₀ 10.8 µM and clogP 2.85) and compound 19 (IC₅₀ 10.0 µM and clogP 3.12). Compound 21 (IC₅₀ = 12.8 µM and clogP = 2.66) also exhibited activity close to that of the reference compound. Nonetheless, the anti-L. infantum activity observed in this series was generally moderate to low, suggesting that this class is more promising against T. cruzi. Additional studies will be conducted to evaluate improvements in the in vitro pharmacokinetic profile, as well as in vivo antiparasitic activity of the most potent and pharmacokinetically favorable compounds.