Search Results (571)

Background/Objectives: Postharvest fungal decay caused by Botrytis cinerea and Monilinia fructicola poses major threats to global fruit security. Driven by the need for sustainable crop protection agents, this work presents the systematic synthesis, biological evaluation, and computational modeling of a comprehensive 33-compound library of 3-acyl-bromoindole regioisomers (series 4a–k, 5a–k, and 6a–k) to establish clear structure–activity relationship (SAR) design rules. Methods: The regioisomeric library was assembled via a microwave-assisted catalytic protocol in an ionic liquid, expanding the known chemical space with seven newly synthesized 4-bromoindole derivatives (4d–f, 4h–k). Primary in vitro data were modeled using Hansch QSAR and Principal Component Analysis (PCA). Postharvest in vivo efficacy was evaluated on fresh ‘Lapins’ sweet cherries inoculated with M. fructicola. Molecular docking and 100 ns molecular dynamics (MD) simulations were performed against succinate dehydrogenase (SDH) and M. fructicola catalase 2 (MfCat2). Results: In vitro screening demonstrated marked target selectivity: parent core 4 displayed high mycelial suppression against M. fructicola (EC₅₀ = 7.05 µg/mL), whereas C3-acylation with a four-carbon linear chain (4c) achieved optimal broad-spectrum dual action (98% and 86% spore germination inhibition). In vivo cherry bioassays proved that bromoindoles 4, 6a, and 6d significantly suppressed Brown Rot severity to 44–47% (a 20–27% reduction vs. untreated control). Docking and MD trajectories confirmed stable multi-target binding within SDH and MfCat2 active sites (RMSD < 2.0 Å). Conclusions: Bromine regiochemistry dictates pathogen selectivity and life-stage targeting. The novel 4-bromoindole derivatives and multi-target profile establish these scaffolds as promising leads for postharvest crop protection. Full article

Background/Objectives: Diabetes mellitus is a common endocrine disorder characterized by hyperglycemia, which is increasing steadily all over the world. Current medications are limited due to lower efficacy and side effects; therefore, the introduction of novel compounds is crucial to improve therapeutic outcomes for diabetic patients. The objective of this study was to synthesize and evaluate 2-phenyl-3H-quinazolin-4-one and its derivatives for the glucose uptake across the yeast cell membranes, alpha-amylase inhibition, and alpha-glucosidase inhibition in silico and in vitro. Methods: The synthesis of 2-phenyl-3H-quinazolin-4-one and its derivatives was carried out by oxidative cyclocondensation of 2-aminobenzamide (anthranilamide) with various benzaldehydes in the presence of aqueous iron (III) chloride. The synthesized compounds were characterized by melting point determination and spectroscopic techniques, including FTIR, NMR and HRMS. Results: In the glucose uptake by yeast assay, compound 3f had a lower 50% glucose uptake value of 24.02 ± 0.96 mM, compared with the standard drug metformin (25.99 ± 2.41 mM). The alpha-amylase inhibition bioassay showed that compound 3e exhibited very potent inhibition, with an IC₅₀ of 0.43 ± 0.05 mM, compared with the standard drug acarbose (0.53 ± 0.21 mM). Compound 3l exhibited strong alpha-glucosidase inhibition, with an IC₅₀ of 0.42 ± 0.10 mM, compared with the standard drug acarbose (0.29 ± 0.50 mM). Coclusions: These findings suggest the potential of synthesized 2-phenyl-3H-quinazolin-4-one derivatives, 3a–o, as promising candidates for managing diabetes mellitus. However, further studies are required to validate their efficacy and determine their mechanisms of action. Full article

The increasing demand for sustainable agricultural practices has intensified the search for natural alternatives for the control of plant pathogens. This study aimed to evaluate the in vitro inhibitory activity of plant extracts obtained from agro-industrial byproducts, including pomegranate peel (Punica granatum), chestnut peel (Castanea sativa), and grape pomace (Vitis vinifera), against the bacterium Pseudomonas savastanoi and the fungus Colletotrichum fioriniae. Antibacterial activity was assessed using the disk diffusion and Minimum Inhibitory Concentration (MIC) methods. Antifungal activity was evaluated for all extracts through mycelial growth inhibition, spore quantification, and viability assays. Based on its overall antimicrobial performance and extraction yield, the P. granatum extract was selected for evaluation in a detached olive fruit bioassay. The results showed that the pomegranate peel extract exhibited an inhibition halo of $9.80\pm 0.10$ mm against Pseudomonas savastanoi, with a MIC of 5.0 mg/mL and a predominantly bacteriostatic effect. Regarding antifungal activity, the Castanea sativa extract showed the highest inhibition of mycelial growth, reaching 27.27% after 3 days and reducing sporulation by up to 44.36%, whereas the Punica granatum and Vitis vinifera extracts exhibited only moderate inhibitory effects. In the sporulation assay, all extracts reduced spore production and increased early conidial germination, a transient response not accompanied by enhanced fungal development. In the detached olive fruit bioassay, pre-treatment with the P. granatum extract delayed disease progression and reduced final disease severity from 100% in the positive control to 64%, whereas simultaneous application of the extract and the pathogen did not provide a protective effect. Overall, the findings highlight the potential of plant-derived agro-industrial byproducts as sources of bioactive compounds for sustainable plant disease management strategies. Full article

Phosphatidylinositol 5-phosphate 4-kinase type 2 alpha (PIP4K2A) is a key oncogenic driver that regulates the PI5P/PIP2 axis to promote metastatic migration in breast cancer. This study aimed to investigate the therapeutic potential of a crude extract from Tamarix aphylla against breast cancer progression and identify its primary active constituents. The crude extract was initially evaluated against MDA-MB-231 and MCF7 breast cancer cell lines using wound healing assays. Bioassay-guided isolation and screening were deployed to isolate individual components, and the most potent lead compound was structurally characterized using preparative HPLC and FTIR. To analyze its interaction with PIP4K2A, in silico molecular docking, MM/GBSA calculations, and 200 ns molecular dynamics simulations were conducted. In vitro validation was subsequently performed via dose-dependent cytotoxicity assays, scratch assays, single-cell tracking, and RT-qPCR expression analysis. Quercetin was identified as the most potent lead inhibitor against PIP4K2A. Computational modeling revealed that quercetin binds tightly within the PIP4K2A ATP-binding pocket, yielding a superior binding affinity of −10.77 kcal/mol and enhanced thermodynamic stability (ΔGMM/GBSA = −42.6 ± 2.1 kcal/mol) compared to the native ligand (ΔG MM/GBSA = −23.3 ± 1.8 kcal/mol). Molecular dynamics simulations confirmed an induced-fit structural transition that locked the complex into an ultra-stable conformation within a deep global energy minimum basin (−10.8 kcal/mol). In vitro assays demonstrated dose-dependent cytotoxicity, with aggressive triple-negative MDA-MB-231 cells exhibiting higher sensitivity (IC₅₀ = 82.23 µg/mL) than luminal MCF7 cells (IC₅₀ = 97.14 µg/mL). Furthermore, scratch and single-cell tracking assays showed a profound suppression of migration speed and wound closure (reduced to ~40%), while RT-qPCR revealed a near-complete transcriptional knockdown of PIP4K2A mRNA expression (down to 0.025-fold). Collectively, these findings elucidate a unique dual-action mechanism for Tamarix aphylla-derived quercetin—characterized by both direct competitive enzymatic inhibition and downstream transcriptional silencing—positioning it as a promising therapeutic scaffold for targeted anti-metastatic breast cancer interventions. Full article

Background/Objectives: Recent advances in immunotherapy have revolutionized cancer treatment, as exemplified by multiple monoclonal antibodies against programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1). Nevertheless, immunotherapeutic antibodies exhibit certain limitations, which drives the development of alternative approaches, such as small interfering RNA (siRNA)-based therapeutics. The aim of this study was to design and produce new biological PD-L1 siRNA (BioRNA/PD-L1-siRNA) molecules and further define their immunotherapeutic efficacy against non-small cell lung cancer (NSCLC) in vitro. Methods: A novel RNA molecular bioengineering platform was employed to produce new BioRNA/PD-L1-siRNA agents. The functions of BioRNA/PD-L1-siRNAs were determined by quantitative PCR, Western blot, immunofluorescence confocal imaging, flow cytometry, and PD-1/PD-L1 blockade assays in human NSCLC cells, alone and co-cultured with human peripheral blood mononuclear cells (PBMCs). Results: After heterologous overexpression and purification of five BioRNA molecules, one siRNA named BioRNA/PD-L1-siRNA-1 was identified as the most effective to selectively suppress human PD-L1 mRNA and protein levels in H460 and H1975 cells. Disruption of PD-1/PD-L1 interactions by BioRNA/PD-L1-siRNA-1 was further demonstrated via a PD-1/PD-L1 blockade bioassay. In addition, the immunomodulatory effectiveness of BioRNA/PD-L1-siRNA-1 was established in co-culture models, as indicated by the induction of T-cell and natural killer cell populations and an increase in specific cytokines and cytotoxic granules, and subsequent enhancement of apoptosis and greater inhibition of NSCLC cell viability. Conclusions: Overall, these findings demonstrate the potential of bioengineered PD-L1 siRNA entities for NSCLC immunotherapy. Full article

The demand for sustainable nutrients and bioactive compounds has increased interest in underutilized wild plants. Forestiera tomentosa, a Mexican drupe-bearing species, is largely unexplored. This study evaluated the proximate composition, physicochemical and functional properties, phenolic profile, antioxidant capacity, and toxicological safety of F. tomentosa fruit. The fruit showed high carbohydrate content [71.94% dry weight (DW)], with notable crude fiber (7.90% DW), protein (7.39% DW), and lipid (4.30% DW) contents. Analysis revealed a mildly acidic pH (5.66), titratable acidity of 0.32%, and total soluble solids of 2.33 °Brix. The fruit powder had a low water activity (0.42) and a favorable water solubility index (56.10%), oil absorption (4.54%), and foaming capacity (19.71%). The fruit contained high levels of soluble phenols (280.42 mg GAE/g DW), flavonoids (98.89 mg CE/g DW), anthocyanins (54.53 mg C3G/g DW), and condensed tannins (94.05 mg CE/g DW). High-performance liquid chromatography identified 20 phenolic compounds, with 3-(4-hydroxyphenyl) propionic acid, syringic acid, catechin, epicatechin, and gallocatechin being predominant. The fruit showed significant radical scavenging and reducing potential (DPPH, ABTS, and FRAP). Toxicological evaluation using the Artemia salina bioassay showed a 100% survival rate across all concentrations, indicating no acute toxicity. In silico ADMET predictions revealed favorable pharmacokinetic properties, including high intestinal absorption and compliance with Lipinski’s rule of five. These findings position F. tomentosa as a promising, non-toxic source of functional ingredients for the food, nutraceutical, and pharmaceutical industries, supporting biodiversity conservation and sustainable resource utilization. Further studies are needed to evaluate the potential health benefits of this fruit in vitro and in vivo. Full article

Background/Objectives: Plant secondary metabolites remain an invaluable source of novel antibacterial phytochemicals in the fight against antibiotic resistance. The medicinal plant Solidago gigantea Ait. (giant goldenrod) is an invasive species in Europe and represents an abundant, yet largely underexplored reservoir of such bioactive compounds. The primary aim of this study was to perform a non-targeted, effect-directed screening, detection, bioassay-guided isolation, structure elucidation, and microbiological assessment of the antibacterial constituents present in the inflorescences of S. gigantea. Methods: Thin-layer chromatography coupled with direct bioautography (TLC–DB) assay using Bacillus subtilis was utilized for the non-targeted, effect-directed analysis of antibacterial components and the evaluation of in vitro antibacterial activity. Successive preparative flash column chromatography, semi-preparative reversed-phase high-performance liquid chromatography (RP-HPLC), and thin-layer chromatography–mass spectrometry (TLC–MS) were employed for the bioassay-guided fractionation and isolation. The structures of the isolated compounds were elucidated using one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution tandem mass spectrometry (HRMS/MS). The presence of known antibacterial compounds was established via reversed-phase ultra-high-performance liquid chromatography coupled with high-resolution electrospray ionization tandem mass spectrometry (RP-UHPLC–HR-ESI-MS/MS). Results: Two previously undescribed cis-clerodane diterpenoids, the isomeric solidagoic acid L (1) and solidagoic acid M (2), were isolated, identified, and characterized from the ethyl acetate extract of S. gigantea inflorescences. Both compounds exhibited in vitro antibacterial activity against the Gram-positive B. subtilis, confirmed via TLC–DB. In addition, 23 known compounds with antibacterial activity, including 17 clerodane diterpenes, four hydroxylated polyunsaturated fatty acids, and two unsaturated monoacylglycerols, were detected. All of these are reported for the first time in the inflorescences of this plant species. Conclusions: With further optimization, the isolated compounds may represent promising leads for antibacterial drug development. Our findings demonstrate the potential of non-targeted, bioassay-guided approaches for the discovery of novel plant-derived bioactive natural products. Full article

Cuticular wax metabolites on leaf surfaces function as chemical interfaces that modulate the pre-penetration development of phytopathogenic fungi. However, the specific monomeric constituents in grapevine leaf wax that regulate conidial germination and host recognition by grapevine powdery mildew caused by Erysiphe necator remain elusive. Here, we compared leaf cuticular wax characteristics between four susceptible Vitis vinifera cultivars and three resistant Chinese wild Vitis accessions. Scanning electron microscopy coupled with gravimetric analysis revealed that susceptible V. vinifera cultivars exhibited lower wax loads and lamellar crystals, whereas resistant Chinese wild Vitis accessions displayed higher wax accumulation with granular or blocky crystals. Gas chromatography–mass spectrometry profiling further demonstrated divergent compositional patterns: primary alcohols predominated among susceptible V. vinifera cultivars, while aldehydes and alkanes were enriched in resistant Chinese wild Vitis accessions. Paradoxically, in vitro conidial germination assays showed that wax extracts from all grapevines significantly promoted En. NAFU1 conidial germination, indicating that resistance in Chinese wild Vitis accessions is independent of direct wax-mediated inhibition of spore germination. Bioassays of representative monomers revealed that n-triacontane suppressed germination at high concentrations, whereas n-dotriacontanol and stearic acid stimulated it. Collectively, these findings demonstrate that specific cuticular wax monomers exert distinct biological effects on En. NAFU1 conidial germination. Given the ubiquitous presence and concentration-dependent stimulatory activity of stearic acid, we hypothesize that this monomer serves as a conserved chemical cue enabling initial host recognition by En. NAFU1, whereas the differential susceptibility among grapevine genotypes is governed by downstream physical and induced defense mechanisms rather than by variation in stearic acid levels. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, cholinergic dysfunction, and amyloid-β (Aβ) aggregation. Tri-Sannibat-Phol (TSB), a classical Thai polyherbal formulation comprising Piper retrofractum fruit, Ocimum tenuiflorum root, and Piper nigrum root, has been traditionally used for its medicinal properties, yet its anti-AD potential has never been scientifically evaluated. Methods: The therapeutic potential of TSB was investigated through in vitro bioassays including antioxidant, acetylcholinesterase (AChE) inhibitory, and anti-Aβ aggregation assays, alongside neuroprotective evaluation in H₂O₂-induced SH-SY5Y neuroblastoma cells. Acute oral toxicity was assessed in male ICR mice in accordance with OECD Guideline 420. Cognitive-enhancing effects were evaluated using the modified Y-maze, Novel Object Recognition, and Morris Water Maze tests in a scopolamine-induced amnesic mouse model. LC-MS/MS analysis was performed for phytochemical characterization and chemical standardization of the formulation. Results: TSB demonstrated significant antioxidant activity, AChE inhibitory activity, and anti-Aβ aggregation effects, with P. nigrum and O. tenuiflorum identified as the primary contributing components. Neuroprotective effects were confirmed in H₂O₂-induced SH-SY5Y cells, where TSB significantly improved cell viability across concentrations of 1–100 µg/mL. Acute oral toxicity assessment revealed an LD₅₀ exceeding 2000 mg/kg, indicating a favorable safety profile. In vivo behavioral studies demonstrated that TSB at medium-to-high doses significantly reversed scopolamine-induced cognitive deficits across all three behavioral tests. LC-MS/MS analysis identified thirteen piperidine alkaloids, with piperine as the dominant constituent at 17.61 ± 0.80% w/w, proposed as the primary bioactive driver and chemical marker for future quality standardization. Conclusions: These findings suggest that TSB exerts multi-targeted anti-AD effects through complementary mechanisms, supporting its potential as a traditional medicine-based therapeutic candidate for further preclinical and clinical investigation. Full article

Background: Skin aging is driven by oxidative stress and ultraviolet (UV) exposure, leading to extracellular matrix degradation and loss of skin elasticity. This study aimed to identify the most biologically active Citrus species using a bioassay-guided approach and evaluate its potential for dermal applications. Methods: Hydroalcohol extracts and ethyl acetate fractions of Citrus sinensis, Citrus aurantifolia, and Citrus reticulata leaves were screened for antioxidant, enzyme-inhibitory, and polyphenol content. The most active fraction was characterized by UPLC-PDA and LC–MS/MS, formulated into Span-based nanovesicles, and evaluated for physicochemical properties and drug release. Biological activity was assessed using an in vitro scratch wound-healing assay on human dermal fibroblasts and a UVA-induced photoaging mouse model, supported by molecular dynamics simulations. Results: The ethyl acetate fraction of C. aurantifolia (CAE) exhibited the highest biological activity among the tested samples. This fraction showed potent antioxidant activity (DPPH IC₅₀ = 3.53 ± 0.05 µg/mL), marked inhibition of elastase (91.3%), collagenase (92.0%), and tyrosinase (80.2%), and a high total flavonoid content (110.49 mg rutin equivalents/g). Phytochemical profiling of CAE tentatively identified fourteen compounds, predominantly flavonoids, with hesperidin (30.4 mg/g) as a major constituent. The optimized nanovesicles (184 ± 0.9 nm, PDI 0.10, EE% 75.0%) enabled sustained hesperidin release. CAE and CAEnp enhanced fibroblast migration and accelerated wound closure at 24 h (p < 0.05). In vivo, CAEnp improved UVA-induced histopathological alterations and modulated oxidative stress-related markers by reducing p62/SQSTM1 by 28.7%, Keap1 expression to 21% compared with the CAE-treated group, and enhancing Nrf2, ARE, and NQO1 expression by 54.1%, 28.3%, and 57%, respectively. Molecular dynamics simulations supported stable hesperidin binding to elastase and suggested possible modulation of collagenase flexibility. Conclusions: The polyphenol-rich leaf fraction from C. aurantifolia, identified through comparative bioassay-guided fractionation, demonstrated antioxidant, enzyme-inhibitory, wound-healing, and photoprotective effects, particularly after nanoformulation. These findings support its potential for further development as a natural topical anti-aging candidate. Full article

Seaweed-derived biostimulants are increasingly used to improve seed germination and early seedling development in horticultural crops. This study evaluated the effects of five commercially available seaweed extract (SWE) formulations (ASCO, AQUA, KAT, SAGA, and BIO) applied at 2 mL L⁻¹ on germination, seedling growth, biomass accumulation, moisture-related traits, and biomass allocation indices of Capsicum annuum L. under controlled conditions. A 10-day in vitro Petri dish bioassay was conducted using five experimental replicates for each treatment. Significant differences among the treatments were observed for several germination, growth, biomass, and moisture-related parameters. KAT exhibited the highest final germination percentage, whereas SAGA exhibited the fastest germination response and the highest seedling vigor index. SAGA was associated with higher root length and total dry weight, whereas AQUA exhibited among the highest root biomass values. BIO recorded the highest moisture content, leaf length, and shoot-to-root ratio. Correlation analysis identified significant relationships among growth and biomass traits, whereas principal component analysis revealed distinct multivariate response patterns among the evaluated formulations. Overall, the commercial SWE formulations showed different response profiles during the early seedling development of C. annuum under the conditions of present study. Further studies are required to evaluate the consistency of these responses across different concentrations, cultivars, and growing environments. Full article

In this study, a compound with a novel chemical skeleton was isolated and purified from the fermentation broth of Streptomyces canarius SN0246. Its structure was elucidated using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS), and the compound was named canakingmycin. The in vitro antifungal activity of canakingmycin was evaluated against common crop pathogenic fungi, Rhizoctonia solani. The bioassay results showed that canakingmycin exhibited notable inhibitory effects on the mycelial growth of the phytopathogen, with the EC₅₀ value of 76.13 μg/mL. This study enriches the structural diversity of secondary metabolites from Streptomyces and provides a promising lead molecule and scientific basis for the development of new bio-based fungicides. Full article

Commonly occurring polychlorinated biphenyls (PCBs) in the environment have been linked to a broad range of adverse toxicological effects in both animals and humans. In this study, in vitro, in silico, and in vivo models were used to investigate the surface interactions of PCBs with green-engineered clays (GECs). Earlier studies showed that these GECs significantly reduced the toxicities of important planar aromatic chemicals such as benzene and aflatoxin B₁ along with ochratoxin A, a chlorinated aromatic chemical. The overall objective for this study was to show that GECs could tightly adsorb PCBs, resulting in a decrease in toxicity of a commercial PCB mixture (Aroclor 1260). Gastrointestinal pH and temperature were simulated in vitro, and the clay surface binding interactions of six PCBs were characterized using isothermal analyses. Molecular dynamics (MD) simulations were employed to provide atomistic understanding into PCB congener interactions with parent and chlorophyll-amended clays. To confirm the ability of GECs to protect a living organism, Aroclor 1260 was investigated using a well-established hydra bioassay. According to simulations, coplanar PCBs had an increased probability of binding to parent clay compared to non-coplanar ones, in line with experiments, due to their ability to lay flat on the clay surface. Chlorophyll amendments enhanced binding of all PCBs according to both experiments and computations. Within the simulations, chlorophyll amendments facilitated both coplanar as well as non-coplanar PCBs to directly bind to the clay and additionally interact with chlorophyll amendments, as well as to bind to chlorophyll amendments without necessarily interacting with the clay. Aroclor 1260 caused irreversible damage to hydra. At 0.05% inclusion, parent clay offered limited protection (20%) while GECs offered 55% to 65% protection, showing the advantage of GECs over parent clays. The findings of this study indicate that edible GECs adsorb PCBs, with the highest sorption associated with the coplanar congeners. Further studies are warranted to determine the application of GECs as potential disaster-response supplements in the diet to reduce the bioavailability of PCBs from contaminated food and water, especially following floods and other emergencies. Full article

Artemisia campestris is a medicinal plant species endemic to Algeria, particularly abundant in the southern regions and the central Sahara. Its long-standing use in traditional medicine has recently gained scientific attention, prompting further investigation into its bioactive potential. This study focuses on the phytochemical composition and biological activity of its hydromethanolic extract, with a particular emphasis on its ability to inhibit neural enzymes associated with insect physiology with particular relevance to Aphis gossypii (Glover), a major polyphagous agricultural pest. Preliminary screening revealed a diverse array of secondary metabolites, including tannins (catechic and gallic), flavonoids, quinones, glycosides, terpenoids, saponins, coumarins, and alkaloids; however, anthocyanins were not detected. Quantitative analysis confirmed high concentrations of total phenolics (80.91 ± 1.58 mg GAE/g), flavonoids (60.45 ± 2.02 mg RE/g), phenolic acids (4.24 ± 0.38 mg CAE/g), and condensed tannins (2.26 ± 0.29 mg CE/g). Enzyme inhibition assays were performed using Ellman’s method, and IC₅₀ values were calculated by nonlinear regression analysis based on dose–response curves. The extract demonstrated significant in vitro inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀ values of 13.79 ± 0.79 µg/mL and 8.34 ± 0.58 µg/mL, respectively. Molecular docking analyses further confirmed strong binding affinities of cyanidin-3-O-glucoside, malvidin-3-O-glucoside, and apigenin (−8.20 to −8.50 kcal/mol) with the AChE active site, stabilized by hydrogen bonding and π–π interactions with key residues. These results were benchmarked against galantamine, a reference inhibitor, which exhibited IC₅₀ values of 1.50 ± 0.12 µg/mL under the same conditions. Although galantamine showed superior potency, the relatively low IC₅₀ values of the A. campestris extract support its potential as a natural cholinesterase-inhibitory agent warranting further investigation. These findings suggest that A. campestris may represent a promising source of natural cholinesterase inhibitors with potential relevance for eco-friendly insect control. These in vitro and in silico findings provide a mechanistic rationale warranting future in vivo bioassay validation against A. gossypii and related agricultural pests. Full article

Background/Objectives: The emergence of drug-resistant Plasmodium falciparum highlights the need for new antiplasmodial compounds with distinct mechanisms of action. Microbial secondary metabolites, particularly from Streptomyces species, remain important sources of bioactive molecules. This study aimed to evaluate antiplasmodial metabolites associated with a Mongolian Streptomyces isolate. Methods: Streptomyces sp. strain D10 was isolated from Mongolian soil samples and extracted with ethyl acetate. Bioassay-guided fractionation was performed, followed by LC–HRMS analysis and GNPS-based spectral dereplication. Antiplasmodial activity was evaluated against P. falciparum 3D7, K1, and Dd2 strains using a SYBR Green I assay. Cytotoxicity was assessed in HSF cells. Stage-specific susceptibility assays were conducted using synchronized 3D7 parasites. Comparative docking analyses against β-hematin and the chloroquine resistance transporter (PfCRT), together with target prediction and molecular docking analyses, were performed to explore potential mechanisms. In vivo efficacy was evaluated using a Plasmodium yoelii 17XNL mouse model. Results: Fractionation yielded an active fraction (C2), and LC–HRMS and GNPS-based dereplication suggested a bile acid-like metabolite, with ursodeoxycholic acid (UDCA) returned as a putative spectral library candidate associated with fraction C2. Fraction C2 and UDCA showed comparable antiplasmodial activity against P. falciparum 3D7 (IC₅₀ = 6.55 ± 3.00 and 4.68 ± 0. 65 µg/mL, respectively) without detectable cytotoxicity up to 200 µg/mL. Activity was retained against multidrug-resistant K1 and Dd2 strains. Stage-specific assays demonstrated inhibitory activity across ring, trophozoite, and schizont stages without significant stage-dependent differences. Comparative docking analyses suggested interaction profiles distinct from chloroquine in β-hematin and PfCRT models. Additional docking analyses identified PfGluPho, PfMAPK, and PfPFT-β as potential targets. In vivo, UDCA reduced parasitemia in a dose-dependent manner without significant toxicity. Conclusions: UDCA exhibited moderate antiplasmodial activity across in vitro, in silico, and in vivo evaluations with a favorable selectivity profile, supporting further investigation of bile acid-like metabolites as potential antimalarial scaffolds. Full article