Instituto de Productos Naturales y Agrobiología

Naegleria fowleri is the etiological agent of primary amoebic meningoencephalitis, a fulminant infection of the central nervous system that leads to death in most cases. Currently, no standardised therapy is available, and existing treatments are limited by inconsistent efficacy and significant toxicity. β-Hydroxy-γ-lactones previously described as trypanocidal and leishmanicidal agents share structural features, a reactive lactone carbonyl and a stereodefined hydroxyl group, that are commonly linked to disruption of redox and mitochondrial homeostasis in protozoan parasites. Based on this precedent, we hypothesised that the same scaffold could also be active against N. fowleri. Fourteen compounds, ten previously reported β-hydroxy-γ-lactones and four newly synthesised α, β-unsaturated-γ-lactones (butenolides, SAM-13 to SAM-16) obtained by β-elimination, were evaluated in vitro against the trophozoite and cyst stages of two N. fowleri strains (ATCC® 30808™ and ATCC® 30215™), together with cytotoxicity assays in murine macrophages (J774A.1) and human SH-SY5Y neuroblastoma cells. SAM-1 and SAM-5 emerged as the most active molecules, with low-micromolar IC₅₀ values against both trophozoites and cysts; their selectivity, however, differed markedly, with SAM-5 showing a substantially wider safety margin (selectivity index up to 12.9) than SAM-1 (selectivity index of 1.2 in neuroblastoma cells), underscoring selectivity as a key parameter for further optimisation. In contrast, three of the four newly synthesised butenolides were essentially inactive (IC₅₀ > 160 μM); the fourth, SAM-14 (derived from SAM-5), retained measurable but poorly selective activity (IC₅₀ = 56.9 μM, SI = 1.35), indicating that the requirement for the free β-hydroxyl group is substituent-dependent and providing an initial structure–activity relationship for this scaffold. Mechanistic assays showed that SAM-1 and SAM-5 induced hallmarks of programmed cell death in N. fowleri trophozoites, including phosphatidylserine externalisation, chromatin condensation, mitochondrial depolarisation, ROS overproduction, and F-actin disorganisation, together with complementary evidence of autophagic vacuole formation. In silico ADME profiling predicted favourable drug-likeness for SAM-1 and SAM-5, including compliance with Lipinski's rule of five, high gastrointestinal absorption and predicted blood–brain barrier permeability, with neither compound predicted to be a P-glycoprotein substrate. Taken together, these findings identify β-hydroxy-γ-lactones as promising, CNS-penetrant scaffolds for anti-Naegleria drug discovery and outline the structural determinants that should guide their future optimisation.

Improving crop performance under water scarcity requires fertilization strategies that not only supply nutrients but also strengthen soil–plant interactions. In this work, we evaluated a compost tea obtained from recycled organic by-products using the “Sistema de Elaboración de Fertilizante Ecológico Líquido” (SEFEL) system, as a multifunctional biofertilizer in tomato (Solanum lycopersicum) and lettuce (Lactuca sativa) grown under well-watered (WW) and deficit irrigation conditions (WD). We explored its capacity to modulate physiological responses, metabolic adjustments and soil microbiota under WW and WD. SEFEL compost tea application consistently promoted plant growth. Tomato plants showed a 63.9% increase in leaf dry weight under optimal irrigation and a 32.6% increase under WD, while root biomass rose by 30.3% and 53.3%, respectively. In lettuce, leaf dry weight increased by 34% under WW and by 23% under WD. Although drought reduced photosynthetic rates in both species, SEFEL compost tea-treated plants maintained higher carbon assimilation and stomatal conductance during prolonged stress, indicating improved physiological adjustment. These responses were accompanied by a greater accumulation of proline and soluble carbohydrates under water deficit. Interestingly, a different activation of the raffinose family oligosaccharides (RFOs) pathway was detected in tomato and lettuce, pointing to species-specific metabolic strategies. Additionally, SEFEL compost tea improved nutrient uptake under both irrigation regimes and promoted shifts in soil microbial communities, suggesting reinforced soil–plant connectivity. Our results indicate that SEFEL compost tea acts as an integrative soil–plant biostimulant, enhancing nutrient acquisition and drought tolerance while contributing to organic waste valorisation within sustainable production systems.

Diseases caused by Leishmania spp. and Trypanosoma spp. parasites provoke thousands of annual deaths. The current treatments exhibit noticeable disadvantages such as low effectiveness, high cost, side-effects, and the occurrence of resistance. Thus, the search for new drugs is mandatory, and diversity-oriented synthesis appears as a useful tool to access libraries of small, structurally diverse, and potentially bioactive compounds in few steps. In this work, a battery of 10 new and highly substituted β-hydroxy-γ-lactones was straightforwardly synthesized from β,γ-unsaturated N-acyl oxazolidin-2-ones and evaluated against Leishmania amazonensis and Trypanosoma cruzi. Six of the compounds were found to exhibit antiparasitic activity against T. cruzi epimastigotes and/or L. amazonensis promastigotes, as well as against the amastigote forms of both parasites; among these, two compounds stood out against L. amazonensis, with selectivity indices (SI) higher than that of the reference drug. Furthermore, these two compounds appear to induce apoptosis-like cell death in L. amazonensis, as suggested by mechanistic studies. It is worth noting that the compound SAM-2 exhibited an SI four times higher than miltefosine, due to its lower toxicity compared to this drug, highlighting its potential as a promising candidate for the development of new therapies.