In Vitro and In Silico Assessments of Curcuminoids and Turmerones from Curcuma longa as Novel Inhibitors of Leishmania infantum Arginase

<b>Background/Objectives</b>: The anti-<i>Leishmania</i> potential of <i>Curcuma longa</i> and its derivatives, such as curcuminoids, is well-established, yet their mechanisms of action remain underexplored. This study investigates the inhibitory effects of <i>C. longa</i> extracts and curcumin on <i>Leishmania infantum</i> arginase, a key enzyme in polyamine and trypanothione biosynthesis, and evaluates their antiparasitic activity. <b>Methods</b>: Extracts were prepared via rhizome successive maceration with hexane (HEXCURC), dichloromethane (DCCURC), and ethanol (ETOHCURC) and chemically characterized by a combination of chromatographic and spectrometric methods. The inhibition of recombinant <i>L. infantum</i> arginase (<i>Li</i>ARG) was assessed by urea quantification, while molecular docking explored interactions between the main compounds annotated in the extracts and the enzyme's active site. Biological activity was tested against <i>L. infantum</i> promastigotes, intracellular amastigotes, and mammalian cells. <b>Results</b>: LC-MS and GC-MS revealed curcuminoids and turmerones as main compounds annotated in the extracts. DCCURC, HEXCURC, and curcumin showed the strongest <i>Li</i>ARG inhibition (IC₅₀ = 10.04, 14.4, and 17.55 μg/mL, respectively). Docking analysis revealed that curcumin, demethoxycurcumin, and bisdemethoxycurcumin bind near the active site, with binding energies of -3.43, -4.14, and -3.99 kcal/mol, respectively. Curcumin demonstrated superior anti-promastigote activity (IC₅₀ = 15.01 μg/mL) and selectivity (SI = 12.7) compared to the extracts. It also significantly reduced amastigote burden in infected macrophages (IC₅₀ = 13.6 μg/mL). <b>Conclusions</b>: This is the first report demonstrating that <i>C. longa</i> extracts and curcumin inhibit <i>Li</i>ARG. These findings support curcumin's potential as a lead compound for developing multi-target therapies against leishmaniasis, combining enzyme inhibition with direct antiparasitic effects.