Search Results (354)

Background/Objectives: The emergence of antimicrobial resistance necessitates the development of new and effective antimicrobial agents. In this study, three different series of imidazole-based chalcones (IBC1-25) were designed and synthesised using a sustainable approach, with the aim of identifying compounds with enhanced antimicrobial activity. Methods: A series of monoalkoxy, dialkoxy, and trialkoxy imidazole-based chalcones (IBC1–25) were synthesised and evaluated for their antimicrobial and antifungal activities against a range of microbial strains. Structure-activity relationships were analysed, and molecular docking studies were performed to investigate potential binding interactions with biofilm-associated regulatory proteins. In addition, ADME properties were predicted to assess drug-likeness. Results: Among the monoalkoxy derivatives (IBC1-14), IBC5 exhibited the broadest spectrum of activity, particularly against S. epidermidis. Several dialkoxy analogues (IBC17-21) demonstrated improved potency, with IBC20 showing notably high activity. While IBC22 and IBC25 were largely ineffective, IBC23 and IBC24 displayed significant antibacterial and antifungal activities. Overall, dialkoxy and trialkoxy derivatives exhibited enhanced efficacy, whereas monoalkoxy compounds with bulky or long-chain substituents were generally less active. The presence of multiple alkoxy substituents, such as methoxy and ethoxy groups, on the phenyl ring significantly improved activity, particularly against fungi and Gram-positive bacteria. Molecular docking studies revealed that IBC20 and IBC23 showed favourable binding to the biofilm-associated regulator TcaR, suggesting a potential allosteric inhibition mechanism, while weak interactions were observed with TagF. ADME predictions indicated good oral absorption and compliance with key drug-likeness criteria. Conclusions: The results demonstrate that both the number and type of alkoxy substituents play a critical role in antimicrobial activity. In particular, IBC20 and IBC23 emerge as promising candidates for further development as antimicrobial agents targeting biofilm-associated pathways. Full article

Chalcones are compounds containing an α,β-unsaturated carbonyl group that have been studied due to their structural simplicity, ease of synthesis, and broad spectrum of biological activities. Within this family, nitrochalcones have gained relevance due to the influence of the nitro group (–NO₂) on the modulation of their electronic properties, chemical reactivity, and pharmacological behavior. This review presents a critical analysis of advances in the biological activities and possible mechanisms of action of nitrochalcones and their derivatives, with an emphasis on their structure–activity relationships and therapeutic potential. The available evidence shows that nitrochalcones and their derivatives act as multitarget molecules, capable of intervening in key biological processes such as oxidative stress, mitochondrial dysfunction, inflammation, and cell signaling pathways associated with proliferation and apoptosis. Several studies report anticancer, anti-inflammatory, antiparasitic, antimicrobial, antifungal, and cardiovascular activities, often with favorable selectivity toward pathological cells over healthy cells. Full article

Morus macroura ‘Panzhihua No. 1’ is a dual-purpose cultivar valued for its edible leaves and fruits. Derived from an ancient mulberry tree, it is a unique local germplasm resource. During asexual propagation, M. macroura exhibits sexual variation closely associated with fruit and leaf yield. To explore the molecular mechanisms of sexual dimorphism and its effects on nutritional traits, we integrated transcriptomic and metabolomic analyses of male and female inflorescences and leaves. Key sex-biased genes were enriched in plant hormone signaling, flavonoid biosynthesis, and carbohydrate metabolism pathways. Female plants had elevated expression of ethylene-responsive transcription factor 1 (ERF1), EIN3-binding F-box proteins (EBF1/2), and Chalcone synthase (CHS) genes and higher levels of bioactive flavonoids, including isoquercitrin and kaempferol derivatives. In contrast, male plants had increased expression of gibberellin 20-oxidase (GA20ox) and DELLA genes and accumulated glycosides, which are beneficial for leaf development. These findings reveal how sex-linked metabolic networks shape mulberry tissue functional profiles, providing molecular targets for breeding. Full article

Monoterpenes (thymol, carvacrol, menthol) and phenylpropanoids (eugenol and cinnamaldehyde) and their related derivatives are naturally occurring bioactive compounds found in essential oils (EOs) and have attracted considerable interest as anticancer agents; however, their direct therapeutic use in cancer treatment is often limited by factors such as low bioavailability, moderate potency, and lack of target specificity. Recent studies have demonstrated that rational structural modification of these EO scaffolds can substantially enhance their anticancer potential. This review critically evaluates the different structural modification strategies applied to EO components, including pharmacophore hybridization, heterocycle incorporation (e.g., triazoles, oxadiazoles, chalcones), esterification, halogenation, metal complexation, and nanoparticle conjugation. The review compares these approaches across the selected EO components, highlighting their impact on anticancer potency, and mechanistic relevance. However, the current evidence base is heterogeneous, with considerable variability in experimental conditions, selectivity assessments, and reliance on in vitro or in silico findings, which limits direct cross-study comparisons and translational interpretation. Overall, structural modification of EO components represents a promising strategy for generating novel anticancer lead compounds, but future progress will depend on standardized biological evaluation, rigorous in vivo validation, and comprehensive pharmacokinetic and toxicity profiling to realistically define their clinical potential. Full article

Michael acceptors, such as chalcones and benzylidenes, are privileged scaffolds for the development of anticancer agents. Taking this into account, we developed a selective Claisen–Schmidt condensation of the dammarane-type triterpenoid hollongdione with pyridine-2-carbaldehyde, enabling controlled synthesis of mono- and bis-substituted triterpenes depending on the reaction conditions. The reaction demonstrated high temperature-dependent regioselectivity, providing C2-mono- 2 or 2,21-bis-substituted 3 triterpenes with yields up to 96% and 95%, respectively. The structures of the newly synthesized triterpene chalcones were elucidated by 1D and 2D NMR spectroscopy and unambiguously confirmed by a single-crystal X-ray diffraction, which established the E configuration of the exocyclic double bond. In biological studies, the bis-2-pyridylidene derivative 3 exhibited a pronounced and broad-spectrum antitumor activity in the NCI-60 panel, inducing cell death in 58 of 59 cancer cell lines. High selectivity toward melanoma, renal, and prostate cancer cell lines was observed, with selectivity indices (SI) of up to 18.82 for melanoma LOX IMVI. In MTT assays, compound 3 displayed a submicromolar cytotoxicity, particularly against the KRAS-mutant PANC-1 cell line (IC₅₀ = 0.22 µM). Anticancer activity was further confirmed in a zebrafish (Danio rerio) xenograft model of human HCT116 colon cancer, where tumor growth inhibition reached 72% without pronounced embryotoxicity (LC₅₀ = 1.4 µM). We have developed an efficient approach for the site-selective modification of hollongdione, providing access to potent anticancer dammarane-type chalcones. The bis-2-pyridylidene derivative 3 emerged as a promising lead compound, demonstrating submicromolar potency, high selectivity towards melanoma, and significant in vivo efficacy in a zebrafish xenograft model. Full article

Background: Xanthohumol (XN), a prenylated chalcone flavonoid derived from hops (Humulus lupulus), is increasingly recognized as a highly pleiotropic natural compound. Objective: We aimed to structure XN’s mechanistic hierarchy with emerging translational relevance across disease areas. Methods: We performed a comprehensive and integrative literature review of XN for its biological and translational effects across cancer, metabolic, neurological, cardiovascular, hepatic, renal, and dermatological disorders. Results: Mechanistically, XN exerts diverse bioactivities by inhibiting major pro-oncogenic and pro-inflammatory pathways, such as NF-κB, PI3K/Akt/mTOR, STAT3, HIF-1α, and selective MAPK cascades, while activating cytoprotective signaling, such as the Nrf2/ARE and AMPK pathways. Through these coordinated actions, XN modulates redox homeostasis, mitochondrial integrity, apoptosis, autophagy, ferroptosis, and inflammatory responses. In oncology, XN demonstrates broad-spectrum anticancer activity in preclinical models by inhibiting proliferation; inducing cell cycle arrest and apoptosis; suppressing epithelial–mesenchymal transition, angiogenesis, and metastasis; and restoring chemosensitivity in resistant cancers, including breast, lung, gastric, liver, and head-and-neck carcinomas. Beyond cancer, XN exhibits multi-organ protective bioactivities through antioxidative, antimicrobial, antiviral, and anti-inflammatory activities; inhibition of ferroptosis and excitotoxicity; and preservation of mitochondrial integrity. It shows beneficial effects in preclinical models of Parkinson’s disease, Alzheimer’s disease, hepatic steatosis and fibrosis, renal ischemia–reperfusion injury, cardiovascular dysfunction, skin photoaging, and atopic dermatitis. Human subject studies demonstrate that XN is safe and well tolerated, with observed reductions in oxidative DNA damage and inflammatory cytokine release. Recent advances in micellar formulations have improved XN’s systemic bioavailability and thus its translational feasibility. Conclusions: In summary, XN is a safe, multifunctional natural compound with strong potential for modulating disease-relevant biological pathways associated with cancer, neurodegenerative diseases, metabolic disorders, and inflammatory skin conditions. Continued efforts to enhance its bioavailability and conduct rigorous clinical trials are essential to fully establish its clinical relevance in patient populations. Full article

Chalcone-based derivatives were designed as dual-acting ligands targeting the histamine H₃ receptor (H₃R) and monoamine oxidase B (MAO-B), based on the lead compound DL76. Three series of compounds (1–18) were synthesised and characterised, including simple chalcones (1–9) and piperidinyl chalcones (10–18). All piperidinyl derivatives exhibited nanomolar affinity for human H₃R (hH₃R), with compounds 10–12 achieving K_i values ≤ 30 nM. Simple chalcones showed potent human MAO-B (hMAO-B) inhibition (IC₅₀: 0.85–337 nM), especially 3,4-dichloro derivatives. Compound 15 was the most active hybrid, with a K_i of 46.8 nM for hH₃R and an IC₅₀ of 212.5 nM for hMAO-B. Molecular docking and 250 ns simulations revealed stabilising interactions at both binding sites and clarified structural features behind dual activity. Preliminary ADMET profiling showed low Caco-2 permeability and rapid microsomal metabolism, mainly via hydroxylation. Compound 15 exhibited micromolar cytotoxicity in SH-SY5Y and HepG2 cells, induced G2/M arrest, disrupted mitochondrial homeostasis, and was genotoxic in Peripheral Blood Mononuclear Cells (PBMCs). Additionally, for H₃R ligands (15, DL76, pitolisant), the study reports the first use of Surface Plasmon Resonance Microscopy (SPRM) to assess their interactions with this receptor. Therefore, piperidinyl chalcones show promise as ligands with dual action on H₃R and MAO-B, useful in the treatment of neurodegeneration and/or CNS cancers. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible interstitial lung disease characterized by progressive scarring of the lungs. The available therapeutic strategies are limited and primarily focus on slowing disease progression rather than achieving fibrosis reversal. Cardamonin (CDN), a food-derived natural chalcone, has exhibited anti-fibrotic activity in liver and kidney fibrosis models; however, its role and underlying mechanism in IPF remain unelucidated. Herein, we integrated network pharmacology, machine learning, molecular simulations, and in vitro experiments. Network pharmacology identified 135 overlapping targets between CDN and IPF, which demonstrated a significant enrichment in the Phosphatidylinositol 3-Kinase/Protein Kinase B signaling pathway (PI3K/AKT). Machine learning further prioritized 6 core targets, with IGF1 emerging as a key candidate. Molecular docking revealed a favorable binding energy of −7.9 kcal/mol for the CDN-IGF1 complex. Subsequent 100 ns molecular dynamics simulations further confirmed its robust binding stability, yielding a mean binding free energy of −150.978 kcal/mol. In vitro, CDN significantly mitigated fibrosis in bleomycin (BLM)-challenged A549 cells, downregulating the expression of α-smooth muscle actin (α-SMA) and fibronectin. This effect was accompanied by a beneficial reversal of epithelial–mesenchymal transition (EMT), as indicated by increased E-cadherin levels and decreased vimentin expression. Mechanistically, CDN significantly suppressed the IGF1/PI3K/AKT axis; this inhibitory effect was partially reversed by exogenous IGF1 supplementation and further enhanced by the PI3K-specific inhibitor LY294002. This work provides the evidence that CDN alleviates BLM-induced pulmonary fibrosis by targeting the IGF1/PI3K/AKT-EMT axis. These findings lend support to a robust mechanistic basis for developing CDN as a potential therapeutic candidate for IPF. It should be noted that these conclusions are drawn from in vitro experiments using A549 cells, and further validation in primary alveolar epithelial cells and animal models is warranted to confirm their physiological relevance. Full article

Prostate cancer (PCa) is the second most prevalent cancer among men and a major cause of cancer-related mortality worldwide. Despite an initial favorable response to hormone-based therapies, many patients ultimately develop an advanced and lethal form of the disease, referred to as castration-resistant PCa (CRPC). CRPC is associated with poor prognosis and a lack of effective curative treatments. As a result, new alternatives or improved therapeutic strategies to combat this life-threatening condition are urgently needed. Chalcones, also referred to as 1,3-diphenyl-2-propen-1-ones, have attracted significant attention because of their potent antitumor properties. Owing to their distinctive chemical structure and diverse biological activities, these compounds are promising candidates for treating various cancers, including PCa. Both naturally occurring and synthetically derived chalcones have demonstrated anticancer potential by modulating key cellular processes, including apoptosis, cell cycle regulation, cell migration, invasion, metastasis and angiogenesis, as well as major signaling pathways, such as PI3K/Akt/mTOR, androgen signaling, and NF-κB. This review aims to outline the recent advances in the therapeutic potential of chalcone derivatives in prostate cancer, with a focus on their molecular targets, mechanisms of action, and translational relevance. Full article

The increasing emphasis on green chemistry and environmentally responsible organic synthesis highlights the need to evaluate not only the biological activity but also the ecological safety of bioactive molecules. Xanthone, cinnamic acid, and chalcone scaffolds are widely explored in pharmaceutical and cosmetic research, yet their environmental profiles remain insufficiently characterized. This study assessed the ecotoxicity of simple derivatives from these three structural classes using the Microtox assay with the bioluminescent bacteria Aliivibrio fischeri. Test compounds were synthesized or obtained commercially, dissolved in dimethyl sulfoxide (DMSO), and evaluated at two exposure times (5 and 15 min), with half maximal effective concentration (EC₅₀) values calculated based on luminescence inhibition. The results revealed substantial differences between the investigated groups: chalcone derivatives exhibited uniformly high ecotoxicity, whereas cinnamic acid derivatives showed the most favorable environmental profile with low variability in EC₅₀ values. Xanthone derivatives displayed the widest ecotoxicity range, with toxicity strongly dependent on substituent type and substitution position. Notably, chloro-substitution in cinnamic acid derivatives correlated with lower toxicity, while positional effects were critical in the xanthone series. A comparison with in silico predictions generated using the ADMETlab platform showed poor correlation with the experimental outcomes. The predictive model did not distinguish the differing ecotoxicological behavior of α,β-unsaturated systems in chalcones versus cinnamic acids and systematically flagged halogenation as a toxicity-driving feature, contrary to several of our in vitro observations. Together, these findings provide new insights into structure–ecotoxicity relationships and underscore the need to complement computational predictions with validated experimental assays when designing bioactive compounds with improved environmental safety. Full article

This work aimed to synthesize new derivatives of 2-hydrazinylpyridine-3-carbonitrile and to investigate their biological activity as safeners for the 2,4-D herbicide. The new 2-hydrazinylnicotinonitriles were obtained in high yields (up to quantitative) under mild conditions (25 °C, dioxane) by treating 4,6-diaryl-2-bromo-3-cyanopyridines with hydrazine hydrate. The latter were synthesized by brominating 2-(3-oxo-1,3-diarylpropyl)malononitriles, the Michael adducts, which are readily available from 1,3-diarylpropenones (chalcones) and malononitrile. An unusual side product of the bromination/carbocyclization was isolated and characterized; it consisted of co-crystals of 3-benzoyl-4-hydroxy-4-phenyl-2,6-di-(p-tolyl)cyclohexane-1,1-dicarbonitrile and 3-benzoyl-5-bromo-4-hydroxy-4-phenyl-2,6-di-(p-tolyl)cyclohexane-1,1-dicarbonitrile at a ~4:6 ratio. The new 2-hydrazinylnicotinonitriles react with halogen-containing aromatic aldehydes to form the corresponding hydrazones. The biological activity of the new nicotinonitriles was examined for their function as 2,4-D antidotes. It was found that, under laboratory conditions, eight of the synthesized compounds exhibited a notable antidote effect against 2,4-D on sunflower seedlings. Full article

Dengue virus (DENV) and Zika virus (ZIKV) are flaviviruses transmitted by Aedes spp. mosquitoes, causing a spectrum of symptoms ranging from mild fevers and joint pain to severe damage to vital organs, including the kidneys, brain, and liver. Unfortunately, there are currently no specific treatments for these viruses. The NS2B/NS3 serine protease has been recognized as a crucial therapeutic target due to its pivotal role in viral replication. Herein, several molecular modeling techniques were employed to search for novel allosteric inhibitors against DENV and ZIKV NS2B/NS3 proteases from a set of 545 in-house compounds. Virtual screening based on molecular docking and MM/GBSA-based free energy calculations indicated that, among 545 derivatives, four compounds demonstrated high binding affinity against both targets, including two sulfonamide-vinyl sulfone hybrids (cpd48_e and cpd50_e), one sulfonamide-chalcone analog (cpd48), and one berberine-cinnamic acid derivative (DN071_f). Their molecular complexation was driven mainly by van der Waals forces rather than electrostatic attraction. Several residues at the enzyme allosteric site, particularly K74, L149, and N152 (DENV) and L76, I123, N152, and V155 (ZIKV), were identified as binding hotspots for the screened compounds. Drug-likeness predictions based on Lipinski’s rule of five further supported their potential as drug candidates. Overall, these findings provide valuable insights for the future design and development of novel antiviral drugs targeting the DENV and ZIKV NS2B/NS3 proteases. Full article

The purpose of this study was to present a chemical analysis of the metabolome of cell aggregates of the tree fern Cyathea smithii (J.D. Hooker) cell suspension culture. The LC/MS and GC/MS techniques were used for identification of metabolites. The kinetics of fresh weight, dry weight, and ash content showed 3.5-fold increases during 15-day-long culture. The analysis demonstrated high metabolic activity of cultured cells. In total, 160 metabolites from primary and secondary metabolism and almost 2000 compounds of unknown identity were identified. Three flavonoids—the chalcone isookanin [(2S)-2-(3,4-dihydroxyphenyl)-7,8-dihydroxy-2,3-dihydrochromen-4-one], a methoxy derivative of the flavone gardenin B (5-Hydroxy-2-(4-methoxyphenyl)-6,7,8-trimethoxy-4H-1-benzopyran-4-one), and the isoflavone tectoridin (4′,5-Dihydro-6-methoxy-7-(O-glucoside)isoflavone)—had not been previously detected in the cell culture of C. smithii. Principal component analysis revealed five distinct groups of samples; groups 4 and 5 showed the greatest similarity and corresponded to cultures on days 12 and 15, respectively. The number of differentiating compounds was 75, indicated by a heatmap showing positive and negative correlations between the days of culture. The studies described in this paper are crucial for further identification of metabolites and establishing the relationship between the metabolic composition of tree fern cells in culture and their biological activity, assessed by physiological parameters. By determining the relationship between the chemical composition of cells and their growth from culture initiation to senescence, we will provide a more complete picture of the potential for environmental factors to regulate this relationship. Based on previous studies, environmental stimuli such as electromagnetic fields or light of different wavelengths can result in altered growth physiology and cell mass, as well as metabolite diversification and accumulation. The research results presented in this paper provide a foundation for further studies aimed at predicting and regulating the productivity of C. smithii cells in suspension culture and elucidating the significance of tree fern-derived metabolic products in human cell biology, particularly in thyroid cells. Full article