Antifungal Activity and Action Mechanism Study of Coumarins from Cnidium monnieri Fruit and Structurally Related Compounds.

The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC50 value of 21 µg mL-1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the ß-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner in vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.

Acaricidal activity of strophanthidin derivatives against Psoroptes cuniculi and their inhibitory effect on Na+-K+-ATPase.

In our previous studies, we found that as the active gradients of Adonis coerulea, cardenolides and cardiac glycosides presented toxicity against mites by inhibiting Na+-K+-ATPase. In this paper, after evaluating the acaricidal activity of the commercial cardiac aglycones/glycosides, serials of novel strophanthidin derivatives were designed and synthesized with an efficient and simple route under mild conditions, and their toxicity against mites, the cytotoxicity and inhibitory effect on Na+-K+-ATP enzyme in PC12 cells were investigated. Results showed among of all compounds, including 9 commercial agent and 32 synthesized strophanthidin derivatives, QXG-1 presented the strongest toxicity against mites with the LC50 value of 320.0 µg/mL. C-19 group of strophanthidin substituted with glycinemethylester would increase the toxicity against mites, and the hydroxyl group at C-5 play the vital role in terms of the toxicity. At the given concentration, QXG-1 displayed the safety against PC12 (10.0 µg/mL) in vitro and mice (3.2 mg/kg) in acute toxicity test, and strong inhibitory effect on Na+-K+-ATPase. It could be used as a promising acaricidal agent. This study lays the foundation to develop of QXG-1 as a relatively safe and alternative acaricidal agent.

High Value-Added Application of Two Renewable Sources as Healthy Food: The Nutritional Properties, Chemical Compositions, Antioxidant, and Antiinflammatory Activities of the Stalks of Rheum officinale Baill. and Rheum tanguticum Maxim. ex Regel.

Rhubarb plants (Rheum officinale and R. tanguticum) have edible stalks. In this work, we aimed to compare the nutritional properties, chemical compositions, and bioactivities of R. officinale (SRO) and R. tanguticum (SRT) stalks and to analyze the composition-function relationship. Results showed that the two stalks were good sources of fiber, as well as minerals. They contained abundant essential amino acids and essential fatty acids to regulate the immunity and prevent some chronic diseases; the contents of polyunsaturated fatty acids were 2,244.32 mg/100 g and 2,844.69 mg/100 g, respectively. The antioxidant activity were also proved. Metabolomics showed that SRO and SRT contained abundant phenolic acids. Due to the higher concentrations of flavones, SRT has better antiinflammatory activities than SRO by inhibiting NF-κB signaling pathway. Rhubarb stalks exhibited good safety in acute toxicity and cytotoxicity tests. This work indicated that the two stalks have nutritional value, safety, and bioactivities, and could be used as sources of nutritional ingredients for regulating the immunity of body in food industry.

The acaricidal mechanism and active compounds against Psoroptes cuniculi of the methanol extract of Adonis coerulea Maxim II: Integrated proteomics and SPR analysis.

Adonis coerulea Maxim. as a folk medicine, presented acaricidal acitvity. However, the mode of action and active compounds were unclear. In this study, using proteomics and surface plasmon resonance (SPR) technology the mode of action and active compounds of A. coerulea were investigated, as well as a sensitive and environmentally friendly analytical method developed. Proteomics analysis results showed that after treatment of mites with A. coerulea methanol extract (MEAC), 135 proteins were differentially expressed, most of them enriched in the myocardium pathway and participated in the function of the inflated cystic organ. Na+-K+-ATPase may be a potential target. Then, it was used as a target to capture the compounds from the extract using a SPR test. Twelve compounds were found, five compounds, namely ellagic acid, ouabain, convallatoxin, strophanthidin and cymarin presented the higher affinity with Na+-K+-ATPase in molecular docking test. Further study showed that the latter four compounds presented the stronger cytotoxicity and the inhibitory effect on Na+-K+-ATPase with IC50 values ranging with 2.38-0.56 µg/mL, and also showed toxicity against Psoroptes cuniculi. These results indicated that MEAC presented toxicity against mites by inhibiting Na+-K+-ATPase, and cardiac glycosides may be active compounds of this plant in terms of its acaricidal activity. Only 10 g of plant was used to investigate its active compounds. This study lays the foundation for developing sensitive methods for active compound detection.

Biologically active isoquinoline alkaloids covering 2014-2018.

Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.

New life for an old drug: In vitro and in vivo effects of the anthelmintic drug niclosamide against Toxoplasma gondii RH strain.

Toxoplasma gondii is the causative agent of toxoplasmosis and causes serious public health problems. However, the current treatment drugs have many limitations, such as serious side effects. Niclosamide is a salicylanilide drug commonly used to treat worm infections. Herein, the effectiveness of niclosamide for the treatment of T. gondii infection was demonstrated. This study was to evaluate the in vitro and in vivo activities of niclosamide against T. gondii and to explore its mechanism of action. The in vitro cytotoxicity of niclosamide on human foreskin fibroblast cells was evaluated by MTT test. Niclosamide displayed low host toxicity and its 50% inhibitory concentration was 8.3 µg/mL. The in vitro anti-proliferation and anti-invasion effects of niclosamide on T. gondii were determined by quantitative PCR and Giemsa staining. Niclosamide also inhibited T. gondii tachyzoite proliferation, with a 50% effective concentration of 45.3 ng/mL, and reduced the invasion of cells by tachyzoites (17.8% for the parasite control versus 1.9% for the niclosamide group treated with 100 ng/mL). A model was established by infecting BALB/c mice with the virulent RH strain of T. gondii and used to determine the in vivo effects of niclosamide on acute infection. The mice infected with tachyzoites and treated with 160, 200 or 240 mg/kg·bw niclosamide for 7 days exhibited 20%, 40% and 50% survival, respectively. In addition, niclosamide reduced the parasite burden in the blood and tissues of acutely infected mice, and niclosamide induced decreases in the mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP) levels in extracellular tachyzoites, as assessed by laser confocal microscopy and a multilabel reader. These findings indicated that the mechanism of action of niclosamide might be associated with T. gondii mitochondria oxidative phosphorylation. In conclusion, our results support the efficacy of niclosamide as a potential compound for the treatment of T. gondii infection.

Engineering of Peglayted Camptothecin Into Nanomicelles and Supramolecular Hydrogels for Pesticide Combination Control.

As a famous quinoline alkaloid, camptothecin (CPT) presented the significant anti-tumor activity, as well as the interesting insecticidal activities, but the low solubility, poor hydrophobicity and cuticular penetration of CPT have been severely limited the field application. In this study, we conjugated the camptothecin with polyethylene glycol, forming amphiphilic copolymer, mPEG-CPT, which could be self-assembled into micelles, or formed a hydrogel with α-CD by super-cross-linking to combine delivery with acetamiprid or nitenpyram. Results showed that the nitenpyram or acetamiprid loaded hydrogels showed dual phase release behavior, while the micelles displayed a synchronous and fast release profile. Moreover, these four nanopesticides showed potent or superior insecticidal activities and a synergetic effect against Brevicoryne brassicae, Tetranychus cinnabarinus, and Bursaphelenchus xylophilus. This finding indicated that micelles and hydrogels could be used as effective carriers for pesticide combination control.

Biologically active quinoline and quinazoline alkaloids part II.

To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

Biologically active quinoline and quinazoline alkaloids part I.

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives.

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.