Effects of Naphthoquinones from the Roots of Onosma Armeniacum Klokov on Wound Healing.

In Turkish folk medicine, the roots of Onosma armeniacum Klokov are used to heal wounds, burns, hemorrhoids, hoarseness, dyspnea, stomach ulcers, and abdominal aches. The objective was to evaluate the plant's ethnopharmacological applications using in vivo pharmacological experimental models. In vivo linear incision and circular excision the wound models were used to assess the wound healing activity along with histopathological investigation. The active component(s) were isolated and identified after being exposed to several chromatographic separation procedures on the primary extract. The n-hexane-dichloromethane mixture extract was subjected to chromatographic separation after the wound-healing activity was confirmed. Deoxyshikonin (1), ß,ß-dimethylacrylshikonin (2), α-methyl-n-butylshikonin (3), isovalerylshikonin (4), acetylshikonin (5), ß-hydroxyisovalerylshikonin (6), and 5,8-O-dimethylacetylshikonin (7) were identified as the structures of the isolated compounds. The efficacy of O. armeniacum to heal wounds was investigated in this study. Shikonin derivatives were identified as the primary active components of the roots by bioassay-guided fractionation and isolation procedures.

Evaluation of the antifungal properties of nanoliposomes containing rhinacanthin-C isolated from the leaves of Rhinacanthus nasutus.

Fungal infections represent a challenging threat to the human health. Microsporum gypseum and Trichophyton rubrum are pathogenic fungi causing various topical mycoses in humans. The globally emerging issue of resistance to fungi demands the development of novel therapeutic strategies. In this context, the application of nanoliposomes as vehicles for carrying active therapeutic agents can be a suitable alternative. In this study, rhinacanthin-C was isolated from Rhinacanthus naustus and encapsulated in nano-liposomal formulations, which were prepared by the modified ethanol injection method. The two best formulations composed of soybean phosphatidylcholine (SPC), cholesterol (CHL), and tween 80 (T80) in a molar ratio of 1:1:0 (F1) and 1:1:0.5 (F2) were proceeded for experimentation. The physical characteristics and antifungal activities were performed and compared with solutions of rhinacanthin-C. The rhinacanthin-C encapsulating efficiencies in F1 and F2 were 94.69 ± 1.20% and 84.94 ± 1.32%, respectively. The particle sizes were found to be about 221.4 ± 13.76 nm (F1) and 115.8 ± 23.33 nm (F2), and zeta potential values of -38.16 mV (F1) and -40.98 mV (F2). Similarly, the stability studies of rhinacanthin-C in liposomes demonstrated that rhinacanthin-C in both formulations was more stable in mediums with pH of 4.0 and 6.6 than pure rhinacanthin-C when stored at the same conditions. Rhinacanthin-C in F1 was slightly more stable than F2 when stored in mediums with a pH of 10.0 after three months of storage. However, rhinacanthin-C in both formulations was less stable than pure rhinacanthin-C in a basic medium of pH 10.0. The antifungal potential was evaluated against M. gypsum and T. rubrum. The findings revealed a comparatively higher zone of inhibition for F1. In the MIC study, SPC: CHL: T80 showed higher inhibition against M. gypseum and a slightly higher inhibition against T. rubrum compared to free rhinacanthin-C solution. Moreover, rhinacanthin-C showed significant interaction against 14α-demethylase in in silico study. Overall, this study demonstrates that nanoliposomes containing rhinacanthin-C can improve the stability and antifungal potential of rhinacanthin-C with sustained and prolonged duration of action and could be a promising vehicle for delivery of active ingredients for targeting various fungal infections.

Unlocking the potential of 1,4-naphthoquinones: A comprehensive review of their anticancer properties.

Cancer encompasses a group of pathologies with common characteristics, high incidence, and prevalence in all countries. Although there are treatments available for this disease, they are not always effective or safe, often failing to achieve the desired results. This is why it is necessary to continue the search for new therapies. One of the strategies for obtaining new antitumor drugs is the use of 1,4-naphthoquinone as a scaffold in synthetic or natural products with antitumor activity. This review focuses on compiling studies related to the antitumor activity of 1,4-naphthoquinone and its natural and synthetic derivatives over the last 10 years. The work describes the main natural naphthoquinones with antitumor activity and classifies the synthetic naphthoquinones based on the structural modifications made to the scaffold. Additionally, the formation of metal complexes using naphthoquinones as a ligand is considered. After a thorough review, 197 synthetic compounds with potent biological activity against cancer have been classified according to their chemical structures and their mechanisms of action have been described.

Exploring the Therapeutic Potential of Lawsone and Nanoparticles in Cancer and Infectious Disease Management.

Lawsone, a naturally occurring compound found in henna, has been used in traditional medicine for centuries due to its diverse biological activities. In recent years, its nanoparticle-based structure has gained attention in cancer and infectious disease research. This review explores the therapeutic potential of lawsone and its nanoparticles in the context of cancer and infectious diseases. Lawsone exhibits promising anticancer properties by inducing apoptosis and inhibiting cell proliferation, while its nanoparticle formulations enhance targeted delivery and efficacy. Moreover, lawsone demonstrates significant antimicrobial effects against various pathogens. The unique physicochemical properties of lawsone nanoparticles enable efficient cellular uptake and targeted delivery. Potential applications in combination therapy and personalized medicine open new avenues for cancer and infectious disease treatment. While clinical trials are needed to validate their safety and efficacy, lawsone-based nanoparticles offer hope in addressing unmet medical needs and revolutionizing therapeutic approaches.

Antitumoral photoinduced effects of crude extract, fractions, and naphthoquinones from Sinningia magnifica (Otto & A. Dietr.) Wiehler (Gesneriaceae) in a bioguided study.

Photodynamic therapy (PDT) has been used for various purposes, including as an antitumor resource in a noninvasive therapy with minimal side effects. Sinningia magnifica (Otto & A. Dietr.) Wiehler is a rupicolous plant found in rock crevices in Brazilian tropical forests. Initial studies indicate the presence of phenolic glycosides and anthraquinones in species of the genus Sinningia (Generiaceae family). It is known that anthraquinones are natural photosensitizers with potential PDT applications. This led us to investigate the potential compounds of S. magnifica for use as a natural photosensitizer against the melanoma (SK-MEL-103) and the prostate cancer (PC-3) cell lines in a bioguided study. Our results showed that singlet oxygen production by the 1,3-DPBF photodegradation assay greatly increased in the presence of crude extract and fractions. The biological activity evaluation showed photodynamic action against melanoma cell line SK-MEL-103 and prostate cell line PC-3. These results suggest the presence of potential photosensitizing substances, as demonstrated in this in vitro antitumor PDT study by the naphthoquinones Dunniol and 7-hydroxy-6-methoxy-α-dunnione for the first time. Naphthoquinones, anthraquinones and phenolic compounds were identified in the crude extract by UHPLC-MS/MS analysis, motivating us to continue with the bioguided phytochemical study aiming to discover more photochemically bioactive substances in Gesneriaceae plants.

Euchronin A-F isolated from the Arnebia euchroma (Royle) Johnst. and their anti-proliferative activities in vitro.

Six new naphthoquinones, euchronin A-F (1-6) and nine known naphthoquinones (7-15), were isolated from the roots of Arnebia euchroma (Royle) Johnst. The structures of the new compounds were confirmed by extensive spectroscopic analyses, including UV, IR, HR-ESI-MS, 1D and 2D NMR. In the present study, we estimated the anti-proliferative activities of these compounds with HaCaT cells. The results indicated that compounds 2 and 4 showed strong anti-proliferative activities at 25 µM, with relative viability at 38.83% and 68.44%, respectively.

Quinones: Biosynthesis, Characterization of 13 C Spectroscopical Data and Pharmacological Activities.

Quinones are natural products widely distributed in nature, which are involved in stages of several vital biological processes, with mostly having a variety of pharmacological properties. The main groups comprising most of these compounds are benzoquinones, naphthoquinones, anthraquinones, and phenanthraquinones. Quinone isolation has been a focus of study around the world in recent years; for this reason, this study approaches the junction of natural quinones identified by 13 C Nuclear Magnetic Resonance (NMR) spectroscopic analytical techniques. The methodology used to obtain the data collected articles from various databases on quinones from 2000 to 2022. As a result, 137 compounds were selected, among which 70 were characterized for the first time in the period investigated; moreover, the study also discusses the biosynthetic pathways of quinones and the pharmacological activities of the compounds found, giving an overview of the various applications of these compounds.

Shikonin and Alkannin inhibit ATP synthase and impede the cell growth in Escherichia coli.

Naturally occurring naphthoquinones, shikonin and alkannin, are important ingredients of traditional Chinese medicine Zicao. These constituents are reported to have many therapeutic uses, such as wound healing; scar treatment; and anti-inflammation, anti-acne, anti-ulcer, anti-HIV, anticancer, and antibacterial properties. The primary objective of this investigation was to explore the effect of shikonin and alkannin on Escherichia coli ATP synthase and its cell growth. Shikonin caused complete (100 %) inhibition, and alkannin caused partial (79 %) inhibition of wild-type E. coli ATP synthase. Both caused partial (4 %-27 %) inhibition of ATP synthase with genetically modified phytochemical binding site. The growth inhibition of strains expressing normal, deficient, and mutant ATP synthase by shikonin and alkannin, corroborated the inhibition observed in isolated normal wild-type and mutant ATP synthase. Trivial inhibition of mutant enzymes indicated αR283D, αE284R, ßV265Q, and γT273A are essential for formation of the phytochemical binding site where shikonin and alkannin bind. Further, shikonin was a potent inhibitor of ATP synthase than alkannin. The antimicrobial properties of shikonin and alkannin were tied to the binding at phytochemical site of microbial ATP synthase. Selective targeting of bacterial ATP synthase by shikonin and alkannin may be an advantageous alternative to address the antibiotic resistance issue.

Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo.

P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate U-556, derived from 1,4-naphthoquinone thioglucoside, to inhibit ATP-induced Ca2+ influx and YO-PRO-1 dye uptake, which indicates blocking P2X7R in RAW 264.7 macrophages. This process was accompanied by the inhibition of ATP-induced reactive oxygen species production in macrophages, as well as the macrophage survival strengthening under ATP toxic effects. Nevertheless, U-556 had no noticeable antioxidant capacity. Naphthoquinone-thioglucoside conjugate U-556 binding to the extracellular part of the P2X7R was confirmed by SPR analysis, and the kinetic characteristics of this complex formation were established. Computer modeling predicted that U-556 binds the P2X7R allosteric binding site, topographically similar to that of the specific A438079 blocker. The study of biological activity in in vivo experiments shows that tetracylic conjugate significantly reduces inflammation provoked by carrageenan. The data obtained points out that the observed physiological effects of U-556 may be due to its ability to block the functioning of the P2X7R.

Iseoic acids and bisiseoate: three new naphthohydroquinone/naphthoquinone-class metabolites from a coral-derived Streptomyces.

Two new naphthohydroquinone derivatives designated iseoic acids A (1) and B (2) and a new symmetrical glycerol bisester of naphthoquinonepropanoic acid designated bisiseoate (3) were isolated from the culture extract of a marine-derived actinomycete Streptomyces sp. DC4-5. The structures of 1-3 were determined by analyzing one- and two-dimensional NMR data and MS analytical data. The absolute configurations were determined by NOESY analysis and the phenylglycine methyl ester (PGME) method for 1 and by considering the structural similarity and biosynthesis for 2 and 3. Compound 3 exhibited modest cytotoxicity against P388 murine leukemia cells with an IC50 value of 19 µM.

Participation of Oxidative Stress in the Activity of Compounds Isolated from Eleutherine plicata Herb.

From Eleutherine plicata, naphthoquinones, isoeleutherine, and eleutherol were isolated, and previous studies have reported the antioxidant activity of these metabolites. The present work evaluated the role of oxidative changes in mice infected with Plasmodium berghei and treated with E. plicata extract, fraction, and isolated compounds, as well as to verify possible oxidative changes induced by these treatments. E. plicata extracts were prepared from powder from the bulbs, which were submitted to maceration with ethanol, yielding the extract (EEEp), which was fractionated under reflux, and the dichloromethane fraction (FDMEp) was submitted for further fractionation, leading to the isolation of isoeleutherine, eleutherine, and eleutherol. The antimalarial activity was examined using the suppressive test, evaluating the following parameters of oxidative stress: trolox equivalent antioxidant capacity (TEAC), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH). Furthermore, the molecular docking of naphthoquinones, eleutherol, eleutherine, and isoeleutherine interactions with antioxidant defense enzymes was investigated, which was favorable for the formation of the receptor-ligand complex, according to the re-rank score values. Eleutherine and isoeleutherine are the ones with the lowest binding energy for catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx1), showing themselves as possible targets of these molecules in the involvement of redox balance. Data from the present study showed that treatments with E. plicata stimulated an increase in antioxidant capacity and a reduction in oxidative stress in mice infected with P. berghei, with naphthoquinones being responsible for reducing oxidative changes and disease severity.

Structural and pharmacological diversity of 1,4-naphthoquinone glycosides in recent 20 years.

1,4-naphthoquinones are the most widespread naphthoquinone compounds. Recently, many 1,4-naphthoquinone glycosides with different structural features have been obtained from both nature and synthesis, which has led to an increasing variety of naphthoquinone glycosides. In this paper, the structure variety and biological activity in recent 20 years are reviewed, and classified them according to the source and structure characteristics. Meanwhile the synthetic methods of O-, S-, C- and N-naphthoquinone glycosides and their structure activity relationships are also described. It was referred that the presence of polar groups of C2 and C5 and non-polar groups attached to C3 on the naphthoquinone ring are beneficial for their biological activities. It will provide more comprehensive literature resources for the future research of 1, 4-naphthoquinone glycosides and lay a theoretical foundation.

Synthesis and structure-activity relationship studies of naphthoquinones as STAT3 inhibitors.

Based on previous studies, we synthesized a novel class of ortho- and para-naphthoquinones derivatives bearing a phenolic hydroxy or sulfonamide moiety and evaluated their in vitro antiproliferative and signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitory activities. The biological evaluations of these naphthoquinones revealed that ortho-naphthoquinones containing a phenolic hydroxyl group exhibited greater antiproliferative activity compared to compounds without a phenolic hydroxyl group. Among the synthesized para-naphthoquinones, 21, which has a condensed sulfonamide structure, showed substantially higher antiproliferative activity than that of the parent compound, and was also found to inhibit the phosphorylation of STAT3(Y705) in a dose-dependent manner. A docking simulation using AutoDock Vina suggested that 21 could directly bind to the hinge region of STAT3.

Biological activity of 1,2,3-triazole-2-amino-1,4-naphthoquinone derivatives and their evaluation as therapeutic strategy for malaria control.

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 µM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 µM. Compounds 7, 8 and 11 showed IC50 values < 5 µM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.

Approaches for in vitro propagation and production of plumbagin in Plumbago spp.

The genus Plumbago (family Plumbaginaceae), commonly known as leadwort, is a sub-tropical shrub that produces secondary metabolite plumbagin, which is employed by pharmaceutical companies and in clinical research. Plumbagin is a potent pharmaceutical because of its anti-microbial, anti-malarial, antifungal, anti-inflammatory, anti-carcinogenic, anti-fertility, anti-plasmodium, antioxidant, anti-diabetic, and other effects. This review documents the biotechnological innovations used to produce plumbagin. The use of modern biotechnological techniques can lead to a variety of benefits, including better yield, increased extraction efficiency, mass production of plantlets, genetic stability, increased biomass, and more. Large-scale in vitro propagation is necessary to minimize over-exploitation of the natural population and allow the use of various biotechnological techniques to improve the plant species and secondary metabolite production. During in vitro culture, optimum conditions are requisites for explant inoculation and plant regeneration. In this review, we provide information on various aspects of plumbagin, depicting its structure, biosynthesis, and biotechnological aspects (both conventional and advanced) along with the future prospects. KEY POINTS: • Critical assessment on in vitro biotechnology in Plumbago species • In vitro propagation of Plumbago and elicitation of plumbagin • Biosynthesis and sustainable production of plumbagin.

Impact of cytotoxic plant naphthoquinones, juglone, plumbagin, lawsone and 2-methoxy-1,4-naphthoquinone, on Chlamydomonas reinhardtii reveals the biochemical mechanism of juglone toxicity by rapid depletion of plastoquinol.

Hydrophilic, untethered 1,4-naphthoquinones (1,4-NQs) are plant secondary metabolites that are often excreted into the environment and play a role in various plant-microbial, plant-fungal, plant-insect and plant-plant interactions. The biological activity of 1,4-NQs is mainly related to their redox properties, i.e. the ability to undergo redox cycling in cells. These compounds may also undergo electrophilic addition to thiol-containing compounds. The aim of this study was to compare the impact of juglone, plumbagin, lawsone and 2-methoxy-1,4-naphthoquinone (2-met-NQ) on the antioxidant response of the green microalga Chlamydomonas reinhardtii. The algae were incubated with the examined compounds under low light for 6 h and the content of photosynthetic pigments, prenyllipid antioxidants, ascorbate, soluble thiols, proline, and superoxide dismutase activity was assessed. To examine the interaction between photosynthetic activity and naphthoquinone toxicity, we carried out the second experiment, in which C. reinhardtii was incubated with 1,4-NQs for 1 h under high light or in darkness. The pro-oxidant action of the examined 1,4-NQs depended on their reduction potentials, which decrease in order: juglone > plumbagin > 2-met-NQ > lawsone. Lawsone did not display pro-oxidant properties. Exposure to high light strongly enhanced the pro-oxidant effect of juglone, plumbagin, and 2-met-NQ, which is thought to result from the interception of the electrons from photosynthetic electron transfer chain. Only juglone was able to cause a fast depletion of plastoquinol, which may be an important mode of action of this allelochemical, responsible for its high toxicity to plants.

Novel NQO1 substrates bearing two nitrogen redox centers: Design, synthesis, molecular dynamics simulations, and antitumor evaluation.

By analyzing the crystal structure of NQO1, an additional binding region for the ligand was discovered. In this study, a series of derivatives with a novel skeleton bearing two nitrogen redox centers were designed by introducing amines or hydrazines to fit with the novel binding region of NQO1. Compound 24 with a (4-fluorophenyl)hydrazine substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1972 ± 82 µmol NADPH/min/µmol NQO1 and 6.4 ± 0.4 × 106 M-1s-1, respectively. Molecular dynamics (MD) simulation revealed that the distances between the nitrogen atom of the redox centers and the key Tyr128 and Tyr126 residues were 3.5 Å (N1-Tyr128) and 3.4 Å (N2-Tyr126), respectively. Compound 24 (IC50/A549 = 0.69 ± 0.09 µM) showed potent antitumor activity against A549 cells both in vitro and in vivo through ROS generation via NQO1-mediated redox cycling, leading to a promising NQO1-targeting antitumor candidate.

It Takes Two to Tango, Part II: Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities.

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango!

Epoxy-α-lapachone (2,2-Dimethyl-3,4-dihydro-spiro[2H-naphtho[2,3-b]pyran-10,2'-oxirane]-5(10H)-one): a promising molecule to control infections caused by protozoan parasites.

Natural products and their derivatives have been sources of search and research for new drugs for the treatment of neglected diseases. Naphthoquinones, a special group of quinones, are products of natural metabolites with a wide spectrum of biological activities and represent a group of interesting molecules for new therapeutic propositions. Among these compounds, lapachol stands out as a molecule from the heartwood of Tabebuia sp. whose structural changes resulted in compounds considered promising, such as epoxy-α-lapachone (ELAP). The biological activity of ELAP has been demonstrated, so far, for parasitic protozoa such as Leishmania spp., Trypanosoma cruzi and Plasmodium spp., species causing diseases needing new drug development and adequate health policy. This work gathers in vitro and in vivo studies on these parasites, as well as the toxicity profile, and the probable mechanisms of action elucidated until then. The potential of ELAP-based technology alternatives for a further drug is discussed here.

Pyranonaphthoquinones and Naphthoquinones from the Stem Bark of Ventilago harmandiana and Their Anti-HIV-1 Activity.

Seven previously undescribed compounds, including five pyranonaphthoquinones (ventilanones L-P) and two naphthoquinones (ventilanones Q and R), along with 15 known compounds were isolated from the stem bark of Ventilago harmandiana (Rhamnaceae). The structures were established by extensive analysis of their spectroscopic data. The absolute configuration of ventilanone L was established from single crystal X-ray crystallographic analysis using Cu Kα radiation and from its electronic circular dichroism data. Anti-HIV-1 activity using a syncytium inhibition assay and the cytotoxic activities of some isolated compounds were evaluated. Compounds 12, 13, 15, and 16 showed activity against syncytium formation with half maximal effective concentration (EC50) values ranging from 9.9 to 47 µM (selectivity index (SI) 2.4-4.5).