In vitro and in silico Assessments of curcuminoids and turmerones from Curcuma longa as novel Inhibitors of Leishmania infantum arginase.

In Vitro and In Silico Assessments of Curcuminoids and Turmerones fromas Novel Inhibitors ofArginase.

Flora F S Spíndola, Ana Lúcia T A Pinheiro, Maria Athana Mpalantinos, Josiane C F Silva, Walter S M F Neto, Rodrigo Rodrigues da Conceição, Emiliano de Oliveira Barreto, Barbara A Abrahim-Vieira, Consuelo J Rodrigues, Arthur Soares Souza, Dirlei Nico, Ashley Amaral, Amaia Garcia, Igor A Rodrigues

Pharmaceuticals (Basel)

Jun 5, 2025

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Abstract

: The anti-potential ofand its derivatives, such as curcuminoids, is well-established, yet their mechanisms of action remain underexplored. This study investigates the inhibitory effects ofextracts and curcumin onarginase, a key enzyme in polyamine and trypanothione biosynthesis, and evaluates their antiparasitic activity.: 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 recombinantarginase (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 againstpromastigotes, intracellular amastigotes, and mammalian cells.: LC-MS and GC-MS revealed curcuminoids and turmerones as main compounds annotated in the extracts. DCCURC, HEXCURC, and curcumin showed the strongestARG inhibition (IC= 10.04, 14.4, and 17.55μg/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 (IC= 15.01μg/mL) and selectivity (SI = 12.7) compared to the extracts. It also significantly reduced amastigote burden in infected macrophages (IC= 13.6μg/mL).: This is the first report demonstrating thatextracts and curcumin inhibitARG. These findings support curcumin's potential as a lead compound for developing multi-target therapies against leishmaniasis, combining enzyme inhibition with direct antiparasitic effects.