Search Results (391)

Kigelia africana (“sausage tree”) is an established medicinal plant in African traditional medicine, now recognized for its diverse bioactive constituents and emerging anticancer potential. This study systematically evaluates Kigelia africana fruit extract (KAE) in an in vitro model of HT-29 colorectal carcinoma cells, focusing on its cytotoxic effects, mechanistic impact on protein expression, and synergy with cisplatin chemotherapy. Across 42 oncology-related proteins, covering cell survival, apoptosis, adhesion, invasion, and signaling, KAE demonstrated extensive but typically moderate modulation, while cisplatin produced more pronounced responses in most markers. Protein changes linked to metastasis, therapy resistance, and survival were broadly suppressed, indicating significant antitumor activity. Notably, co-treatment with KAE and cisplatin in HT-29 cells resulted in marked synergistic cytotoxicity, permitting lower cisplatin doses while maintaining efficacy. LC-HRMS analyses revealed 14 metabolites in the extract, including phenolic acids naphthoquinones and iridoids, which may contribute to these effects. Full article

Chagas disease is caused by the protozoan Trypanosoma cruzi, and its current treatment is limited to the use of two nitroderivatives, benznidazole (Bz) and nifurtimox; however, their toxicity often leads to discontinuation, justifying the search for new therapeutic options. The biological activity of quinones has long shown efficacy towards pathogenic microorganisms. In our previous investigations, two naphthoquinones combining ortho- and para-quinoidal moieties exhibited remarkable trypanocidal activity and presented low toxicity to host cells. Here, these two active compounds were further assessed. On trypomastigotes and epimastigotes, brominated (NQ1) and chlorinated (NQ2) nor-beta-lapachone-derived 1,2,3-triazoles were more active than Bz, presenting IC₅₀/24 h values in the range of 0.8 to 3.1 µM. NQ1-treated epimastigotes showed a mitochondrial impairment and reactive oxygen species (ROS) production under electron microscopy and flow cytometry. The in vitro evaluation of both combinations of compounds with Bz indicated an additive interaction. In vivo, oral treatment with NQ1 reduced parasitemia in an acute model, with no evidence of toxicity. The treatment also led to a reduction in myocarditis, decreasing the PR interval in electrocardiographic analysis and reversing the sinus bradycardia caused by infection. These data suggest that T. cruzi mitochondrion are part of the NQ1 mechanism of action. In vivo, this compound presented moderate trypanocidal and promising anti-inflammatory activity. Its combination with Bz could enhance current therapeutic protocols and should be better explored in the future. Full article

Background/Objectives: β-Lapachone and triapine are compounds with recognized antitumor potential—the former is an ortho-naphthoquinone, and the latter a thiosemicarbazone inhibitor of ribonucleotide reductase. This study aimed to synthesize and evaluate new β-lapachone-based thiosemicarbazones (TSC1–TSC6) as potential antineoplastic agents. Methods: Lapachol was isolated from Tabebuia sp. and used to obtain ortho-naphthoquinones (2–4), which served as precursors for thiosemicarbazones (TSC1–TSC6). NMR and HRMS spectra were used to characterize the compounds. Their cytotoxic activity was evaluated in vitro against murine melanoma (B16–F10), colon carcinoma (CT26.WT), and breast cancer (4T1) cell lines, as well as normal fibroblasts (L929). Pharmacokinetic parameters were predicted in silico using ADMETLab 3.0. Results: β-Lapachone exhibited strong cytotoxicity toward tumor cells with moderate effects on normal cells, while thiosemicarbazones of β-lapachone, TSC1, and TSC3 demonstrated lower potency but greater selectivity. The β-lapachone-3-sulfonic acid showed high activity against melanoma and breast cancer cells and low toxicity toward normal cells, indicating tumor selectivity. In contrast, their thiosemicarbazones, TSC2, TSC4, and TSC6, showed weak or no antiproliferative activity. The 3-iodo-β-lapachone was cytotoxic to both tumor and normal cells, whereas its derivative TSC5 demonstrated moderate activity with reduced toxicity. β-Lapachone, β-lapachone-3-sulfonic acid, TSC1, and TSC3 exhibited favorable ADME profiles (QED ≈ 0.61–0.66), suggesting good oral bioavailability. Conclusions: The β-lapachone-3-sulfonic acid and the β-lapachone-based thiosemicarbazones TSC1 and TSC3 emerged as promising lead candidates, combining tumor selectivity, favorable pharmacokinetic properties, and structural innovation for the development of safer and more effective antineoplastic agents. Full article

Background: The reintroduction of colistin has led to the rapid emergence of colistin-resistant strains, significantly diminishing its therapeutic efficacy. This presents a need for effective adjuvants to restore colistin efficacy. Approach: We screened the colistin adjuvants through a high-throughput method and then evaluated their synergistic effects and underlying mechanisms. Results: We identified β,β-dimethylacrylalkannin (β,β-Dim), a naphthoquinone compound derived from Lithospermum erythrorhizon, as a potent colistin adjuvant (fractional inhibitory concentration index (FICI) < 0.5). β,β-Dim enhanced colistin activity against 4 of 6 susceptible strains and all 18 colistin-resistant strains carrying either plasmid-borne mcr genes (mcr-1, mcr-3, mcr-8, and mcr-9) or chromosomal two-component system (TCS) mutations (pmrA/B, phoP, and mgrB). These strains included Klebsiella pneumoniae, Escherichia coli, Salmonella Typhimurium, Pseudomonas aeruginosa, and Acinetobacter baumannii. The combination reduced the minimum inhibitory concentrations (MICs) of colistin by 4–1024-fold (from 512 to ≤2 µg/mL). Mechanistically, colistin-mediated outer membrane permeabilization facilitates β,β-Dim entry. Once internalized, β,β-Dim interacts with cytoplasmic membrane phospholipids and disrupts membrane biofunction. Further analysis showed that LPS transport and efflux pump activity were impaired, leading to LPS accumulation in the cytoplasmic membrane and increased intracellular colistin content. These processes elevated reactive oxygen species (ROS) production and markedly reduced ATP levels. In a murine infection model, β,β-Dim (2 mg/kg) combined with colistin (0.2 mg/kg) markedly increased survival from 20% (colistin alone) to 80%. Conclusions: These findings highlight that β,β-Dim combined with colistin is a promising therapeutic strategy for infections caused by colistin-resistant pathogens. Full article

Background: Tuberculosis (TB) remains a critical global health concern, exacerbated by the emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis. In the search for novel therapeutic agents, naphthoquinones have garnered interest due to their diverse mechanisms of action and potent antimycobacterial activity. In this study, we report the design, synthesis, and biological evaluation of a novel series of eleven naphthoquinone-based derivatives (compounds 22–32), developed through a molecular hybridization strategy targeting shikimate kinase (Mtb-SK) an essential enzyme present exclusively in M. tuberculosis. Methods: The compounds were synthesized via a straightforward and efficient synthetic route, and preliminary screening identified five molecules with significant anti-TB activity. Notably, compound 26, 4-(4-ethoxyphenyl) amino) Naphthalene-1,2-dione, exhibited a minimum inhibitory concentration (MIC) of 21.33 µM, comparable to ethambutol and substantially more potent than pyrazinamide. Results: Molecular docking studies indicated that all active compounds interact favorably within the shikimate binding pocket of Mtb-SK, following the proposed mechanism of action. Additionally, ongoing cytotoxicity assays in HepG2 cells aim to assess the selectivity of these derivatives. Conclusions: These findings support the potential of this new class of naphthoquinones as promising scaffolds for the development of anti-TB agents, contributing to the growing body of research focused on new chemotherapeutic options against tuberculosis. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, demanding the continuous search for novel and more selective chemotherapeutic agents. Quinones, particularly naphthoquinones, constitute a privileged class of redox-active compounds with well-documented antitumor activity. Likewise, thiazoles represent a heterocyclic scaffold widely explored in medicinal chemistry due to their broad pharmacophoric adaptability and diverse biological activities. In this context, this review comprehensively explores the chemical synthesis and anticancer potential of hybrid molecules combining the naphthoquinone and thiazole scaffolds. The hybridization of these pharmacophores has emerged as a powerful strategy to design multitarget antitumor agents. The review summarizes key synthetic methodologies, including Hantzsch, hetero Diels–Alder cycloaddition and multicomponent reactions, leading to structurally diverse hybrids. Particular emphasis is placed on derivatives exhibiting strong cytotoxic effects against a broad spectrum of cancer cell lines (e.g., OVCAR3, MCF-7, A549, HCT-116, HeLa, and Jurkat), low toxicity toward normal cells and well-defined mechanisms of action involving topoisomerase IIα, EGFR, STAT3, and CDK1 inhibition, as well as ROS generation and cell cycle arrest. Among these, certain hybrids displayed nanomolar potency and high selectivity indices, reinforcing their potential as promising lead compounds for anticancer drug development. Full article

The naphthoquinone juglone (5-hydroxynaphthalene-1,4-dione) (1) occurs abundantly in nature, especially in species belonging to the Juglandaceae family. Due to its multifaceted biological activities, this compound is considered a privileged structure in Medicinal Chemistry for the development of new prototypes with several biological and pharmacological actions. However, the regioselective synthesis of 2-substituted juglones is challenging due to the non-symmetric naphthoquinone nucleus. Starting from non-symmetric 2,3-unsubstituted naphthalenes, in this paper we describe two general synthetic routes to juglone derivatives bearing an unsaturated or an oxygenated aliphatic side chain at C(2) or C(3). In an MTT test, a few products were more active than the parent unsubstituted juglone as inhibitors of the viability of human lung cancer H460 and breast cancer MCF-7 cells. The most potent compound featured a 1′-acetoxyhomoprenyl sidechain at the carbon C(2) of juglone. Full article

The reaction of a 2-naphthol-derived Mannich base with the push-pull 5-morpholinopenta-2,4-dienal under acidic conditions unexpectedly afforded (7aR*,7bR*)-7a,7b-dihydro-15H-dibenzo[f,f′]cyclopenta[1,2-b:5,4-b′]dichromene. The structure of this product was unambiguously confirmed by NMR spectroscopy and X-ray diffraction analysis. A plausible mechanism involves the in situ generation of 1,2-naphthoquinone-1-methide, followed by a [4 + 2] cycloaddition and a subsequent interrupted iso-Nazarov cyclization. In this process, the enol tautomer of the resulting fused cyclopentenone is trapped by a second equivalent of the 1,2-naphthoquinone-1-methide, leading to the observed polycyclic framework. Full article

Walnut bacterial blight (WBB), caused by Xanthomonas arboricola pv. juglandis, is one of the most damaging diseases in walnut production, capable of reducing yields by up to 50%. Despite its economic importance, tissue-specific defense mechanisms in walnut fruit remain poorly understood. In this study, we performed an integrative approach with metabolomic and biochemical analyses of walnut fruit responses to WBB, examining primary and secondary metabolites, antioxidant activities, and enzyme dynamics across affected and non-affected tissues of the husk, stalk, as well as kernel pellicle and flesh. Using LC-MS, GC-MS, and spectrophotometric assays, we identified distinct compartmentalized defense strategies. The husk showed strong phenolic-mediated responses, with naphthoquinone levels increasing by 125%. However, oxidative processes in necrotic areas may have reduced the stability of these compounds by 50%. In contrast, affected kernel tissues exhibited lower phenolic activity, suggesting that carotenoids and fatty acids could be involved as a protection mechanism, undergoing early oxidation to help preserve lipid integrity. Antioxidant enzymes were upregulated in husk and kernel pellicle, while volatile terpenes and sugars accumulated in infected tissues, indicating metabolic shifts toward localized defense. Overall, our findings reveal a tissue-specific, multi-layered defense network in walnut fruit that could constitute specific markers associated with disease progression. Full article

The naphthoquinone skeleton is known for broad biological applications and, in particular, for antiparasitic efficacy. As part of our ongoing search for new antiprotozoal naphthoquinone derivatives, we incorporated computer-aided optimization models utilizing physicochemical parameters into our approach. Herein, we report on the synthesis of 21 new benzamido–menadione and naphthoquinone derivatives via the Kochi–Anderson reaction. The antiprotozoal activity of all the synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. Several ligand efficiency metrics, such as LLE, SILE, and FQ, were calculated, and the results were visualized in scatterplots. Almost all of the synthesized benzamido–menadione derivatives exhibited high activity against NF54 (IC₅₀ < 1 µM), with the strongest activity and excellent selectivity observed in the 2-fluoro-5-trifluoromethylbenzamido derivative 2f (IC₅₀ = 0.021 µM, SI = 10,000). Specific ligand efficiency metrics, such as SILE, LLE or FQ, showed a clear correlation with the corresponding antiplasmodial activities. Toxicity predictions confirmed low acute oral toxicity for most compounds, further supporting their potential as safe drug candidates. Our findings highlight the benzamido–menadione scaffold as a viable option for new antiplasmodial drugs. Full article

This study aimed to determine the antifungal activity of various compounds and develop a novel antifungal formulation against fungal pathogens, including Alternaria alternata, Botrytis cinerea, Penicillium expansum, and Rhizopus stolonifer. A total of 32 plant-derived secondary metabolites and three extracts (dichloromethane, ethyl acetate, and methanol) from Lawsonia inermis, Juglans regia, and Drosera intermedia were screened at a concentration of 250 ppm. The chemical composition of the D. intermedia ethyl acetate extract was characterized using chromatographic techniques. Subsequently, an emulsifiable concentrate formulation from this extract was prepared, and its efficacy was evaluated at concentrations ranging from 250 to 2000 ppm. The D. intermedia ethyl acetate extract was found to contain three flavonoids (1.4%) and three naphthoquinones (2.8%). The formulation exhibited optimal effect at 1000 ppm. Overall, the high efficacy of the formulation containing the dried D. intermedia extract (10:1, ethyl acetate) positions it as a promising and viable alternative to synthetic fungicides. Full article

Actinomycetes, especially Streptomyces, are prolific producers of bioactive metabolites, including pigments with potential applications in foods, textiles, cosmetics, and pharmaceuticals. Motivated by increasing concerns about the safety and environmental impact of synthetic pigments, this study aimed to optimize the production of an extracellular pigment-rich fraction from Streptomyces parvulus and to evaluate its bioactivities relevant for cosmeceuticals. A Plackett–Burman design was used to identify key variables influencing metabolite production, followed by optimization with a Box–Behnken design. The pigment-rich fraction was obtained after extraction with ethyl acetate from lyophilized supernatants and chemically characterized by IR and LC–MS. Biological assays were conducted to assess anti-tyrosinase, immunomodulatory, and antimicrobial activities. Temperature, incubation time, and agitation speed were identified as the most significant factors, with optimal conditions of 30 °C, 50 rpm, and 7 days yielding a pigment concentration of 465.3 μg/mL. LC–MS analysis revealed three 1,4-naphthoquinone-containing compounds, annotated as juglomycin Z (1), WS-5995B (2), and naphthopyranomycin (3), as the main constituents. The pigment-rich fraction showed modest anti-tyrosinase activity (10.9% at 300 μg/mL), immunomodulatory effects (TNF-α inhibition up to 36.9% and IL-10 stimulation up to 38.4% in macrophages), and antimicrobial activity against Staphylococcus epidermidis (15.8 mm inhibition halo, 91% growth reduction). The optimized fermentation model enhances pigment yield while reducing resource consumption, and the pigment-rich fraction exhibits multifunctional bioactivities, underscoring its potential as a natural cosmeceutical ingredient. Full article

In vitro cultured biomass of Rindera graeca, a rare endemic plant, is an efficient renewable source of bioactive naphthoquinones, e.g., rinderol, a potential bioactive inducer of apoptosis in cancer cells. Bioengineering strategies, as biomass immobilization on functionalized biomaterial-based scaffolds, elicitation by chitosan, and in situ extraction of metabolites, are tested for intensifying naphthoquinones production in R. graeca hairy roots. The aim of the study was to investigate the effects of hybrid poly(lactic)–chitosan scaffolds on biomass proliferation and rinderol production in R. graeca hairy roots. Effects of chitosan origin (fungal or squid), molecular mass (350–1800 kDa), and concentration (up to 45%) in the developed hybrid scaffolds have been quantitatively identified, and the results were compared to the reference culture system containing an unmodified PLA-based construct. Applying PLA–chitosan scaffold containing 33% of fungal chitosan resulted in 635 times higher rinderol production (3660 µg g_DW⁻¹) than the application of reference scaffolds. Among the tested parameters, the chitosan concentration in the hybrid scaffolds revealed significant importance in rinderol production. To sum up, the developed hybrid PLA-chitosan scaffold may be recognized as a functional key element supporting the production of naphthoquinones in cultures of R. graeca biomass. Full article

Background/Objectives: Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various acute and chronic brain disorders, including epilepsy. Although 1,4-naphthoquinone derivatives have been reported to regulate ferroptosis, their mechanistic roles in the nervous system remain underexplored. Here, we investigated the protective effects of 8-hydroxy-2-anilino-1,4-naphthoquinone (8-HANQ) on ferroptotic neuronal death in vitro and seizure behaviors in vivo. Methods: HT22 hippocampal cells were exposed to ferroptosis inducers including glutamate, glutamate plus iron, or RSL3. Lipid reactive oxygen species (ROS), ferroptosis markers, and its related molecules were assessed by flow cytometry and Western blotting. In a kainate (KA)-induced seizure model, 8-HANQ was delivered intracerebroventricularly, followed by behavioral seizure scoring and analysis of hippocampal levels of PSD95, cathepsin-B, and FGFR1 at 72 h post-seizure. Results: 8-HANQ attenuated ferroptotic death in HT22 cells, reducing lipid ROS accumulation and abnormal acyl-coA synthetase long chain family member 4 (ACSL4), suggesting 8-HANQ’s anti-ferroptotic action. Moreover, 8-HANQ also prevented aberrant STAT3-dependent cathepsin-B overexpression while modulating soluble N-cadherin-mediated FGFR1 activation. In vivo, 8-HANQ decreased KA-induced seizure behavior, restored hippocampal cathepsin-B and PSD95 expression, and partially alleviated dysregulation of FGFR1 activation. Conclusions: 8-HANQ prevents ferroptotic neuronal death and synaptic deficits involving FGFR1/STAT3/cathepsin-B-driven ferroptosis while lowering seizure severity, suggesting that 8-HANQ may serve as a potential anti-ferroptotic and anti-seizure agent. Full article

Exposure to fine particulate matter (PM2.5) poses a major threat to skin health, yet effective prevention strategies remain limited. Shikonin, a naphthoquinone derived from Lithospermum erythrorhizon, exhibits potent antioxidant and anti-inflammatory activities. However, its therapeutic application is limited by low bioavailability. To address this limitation, we developed shikonin-loaded nanoparticles (SH-NPs) using an emulsion solvent evaporation method and characterized their physicochemical properties. The protective effects of SH-NPs against PM2.5-induced skin damage were evaluated in a mouse model. The SH-NPs exhibited favorable characteristics, including a mean particle size of 209.03 ± 2.45 nm, a PDI of 0.064 ± 0.03, and a zeta potential of –17.69 ± 2.06 mV. The encapsulation efficiency is 88% and the drug loading capacity is 5.5%, respectively. In vitro, SH-NPs significantly enhanced cellular uptake in HaCaT cells. In vivo, treatment with SH-NPs significantly improved skin structural disorders, epidermal thickening, and collagen fiber reduction, while downregulating the expression of MMP-2 and MMP-9. Furthermore, SH-NPs increased the expression of SOD1 and SOD2, reduced MDA levels, and decreased the expression of TNF-α, IL-1β, and NO. In conclusion, SH-NPs attenuated PM2.5-induced skin toxicity via enhanced antioxidant, anti-inflammatory, and anti-degradation mechanisms, offering a novel strategy to boost shikonin bioavailability and prevent PM2.5-related skin damage. Full article