Isolating Antipathogenic Fungal Coumarins from Coriaria nepalensis and Determining Their Primary Mechanism In Vitro.

Through bioassay-guided isolation, eight undescribed coumarins (1-8), along with six reported coumarins (9-14), were obtained from Coriaria nepalensis. The new structures were determined by using IR, UV, NMR, HRESIMS, and ECD calculations. The results of the biological activity assays showed that compound 9 exhibited broad spectrum antifungal activities against all tested fungi in vitro and a significant inhibitory effect on Phytophthora nicotianae with an EC50 value of 3.00 µg/mL. Notably, compound 9 demonstrated greater curative and protective effects against tobacco balack shank than those of osthol in vivo. Thus, 9 was structurally modified to obtain new promising antifungal agents, and the novel derivatives (17b, 17j, and 17k) exhibited better effects on Sclerotinia sclerotiorum than did lead compound 9. Preliminary mechanistic exploration illustrated that 9 could enhance cell membrane permeability, destroy the morphology and ultrastructure of cells, and reduce the exopolysaccharide content of P. nicotianae mycelia. Furthermore, the cytotoxicity results revealed that compound 9 exhibited relatively low cytotoxicity against HEK293 cell lines with an inhibition rate of 33.54% at 30 µg/mL. This research is promising for the discovery of new fungicides from natural coumarins with satisfactory ecological compatibility.

Four new pregnane C21 steroids isolated from the roots of Cynanchum auriculatum.

Four new steroids cynansteroid G-I (1-3) and cynansteroid K (4), a new natural product 5,6-deacidizingcaudatin (5), and a known compound glycocaudatin (6), were isolated from the roots of Cynanchum auriculatum. The structures of new compounds were identified by comprehensive spectroscopic analyses, including NMR, HRESI-MS, ECD, UV, and IR spectral data. The cytotoxic activities of all the isolates against two human tumour cell lines (COLO-205 and BGC-823) were screened, unfortunately, which were weaker than positive control.

Synthesis and Antifungal Activity of 2-(2-Benzoxazolyl)-1-arylethanone and 2-(2-Benzoxazolyl)-1-alkylethanone Derivatives.

To discover more effective antifungal candidates, 33 benzoxazole derivatives, were designed, synthesized, and evaluated for their antifungal activity against seven phytopathogenic fungi by the mycelium growth rate method. Among 33 benzoxazole derivatives had thirteen derivatives no reported, and new derivatives C17 exhibited good inhibitory activity against Phomopsis sp. with EC50 values of 3.26 µM. Structure-activity relationship (SAR) of these derivatives analysis indicated that the substituent played a key role in antifungal activity in ortho-, meta- and para- substituted acetophenones. The preliminary mechanistic exploration demonstrated that C17 might exert its antifungal activity by targeting the mycelia cell membrane, which was verified by the observed changes in mycelial morphology, the formation of extracellular polysaccharides, cellular contents, cell membrane permeability and integrity, among other effects. Furthermore, C17 had potent curative effect against Phomopsis sp. in vivo, which indicated that C17 may be as a novelty potent antifungal agent.

Synthesis and Antifungal Activity of Curcumol Derivatives.

To discover novel and effective antifungal candidates, a series of new curcumol derivatives were designed, synthesized, and evaluated their antifungal activity against five phytopathogenic fungi by the mycelium growth rate method. Derivatives c4, c22 and c23 exhibited excellent antifungal activity against Phomopsis sp. with EC50 values of 3.06, 3.07, and 3.16 µM, respectively. Specifically, compound c4 exhibited the strongest antifungal activity against Phomopsis sp., which was 44 times that of pyrimethanil (EC50 =134.37 µM). The results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) indicated that compound c4 could cause cell senescence and death of Phomopsis sp. by changing the normal hyphal morphology and disrupting the normal metabolism of hyphal cells. Moreover, compound c4 showed excellent curative effect against Phomopsis sp. on kiwifruit. These findings confirmed that compound c4 has great potential as a potent antifungal agent.

Chemical Constituents of Primulina eburnea (Gesneriaceae) and Their Cytotoxic Activities.

Two new ursane-type triterpenes, eburnealactones A and B (1 and 2), one new flavonoid, eburneatin A (6), and one new phenylethanoid glycoside, chiritoside D (7), along with 9 known compounds (3-5, 8-13) were isolated from the whole plant of Primulina eburnea. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HR-ESI-MS). All the compounds were evaluated for their cytotoxic activities. Compound 1 showed significant cytotoxic activities against MKN-45 cell lines and 5637 cell lines with the IC50 values of 9.57 µM and 8.30 µM, respectively. Compound 1 exhibited moderate cytotoxic activities against A549 and PATU8988T cell lines with the IC50 values of 30.70 µM and 38.22 µM, respectively. Compound 6 exhibited moderate cytotoxic activities against MKN-45, HCT116, PATU8988T, 5637 and A-673 cell lines with the IC50 values of 19.69 µM, 16.44 µM, 18.07 µM, 11.51 µM and 18.15 µM, respectively. Compound 5 showed moderate cytotoxic activities against A549 cell lines with the IC50 values of 24.06 µM.

Quinoline Alkaloids from the Roots of Orixa japonica with the Anti-Pathogenic Fungi Activities.

A new quinoline alkaloid, 5-hydroxy-6-methoxy-N-methyl-2-phenylquinoline-4-one (1), and seventeen known quinoline alkaloids (2-18) were isolated from the roots of Orixa japonica. The structure of 1 was determined by analysis of spectroscopic data. Among them, compounds 2, 3, and 13 were isolated from this plant for the first time. All isolates were screened for the anti-pathogenic fungi activities, including Rhizoctonia solani, Magnaporthe oryzae, and Phomopsis sp. The results showed that five compounds (4, 8, 10, 11, and 12) exhibited significant anti-pathogenic fungi effects at 50.0 µg/mL. In special, compound 10 exhibited the best antifungal activities toward R. solani and M. oryzae with the IC50 values of 37.86 and 44.72 µM, respectively, better than that of the positive control, hymexazol (IC50 121.21 and 1518.18 µM, respectively). Moreover, eleven new quinoline alkaloids derivatives (12a-12k) were designed and synthesized to investigate the structure-activity relationships (SARs). The SARs analysis indicated that the furo[2,3-b]quinoline skeleton and the methoxy at C-7 (compounds 8, 11, and 12) played a key role for improving the antifungal activities.

Maillard Reaction Products with Anti-Tobacco Mosaic Virus Activities Generated in Processed Thermopsis lanceolata R. Br. Seed Extract.

Six novel Maillard reaction products (MRPs) (1-6) were isolated from the processed Thermopsis lanceolata R. Br. seed extract, along with one biogenetically related intermediate (7). Compounds 1-4 possessed three rare dimerization patterns constructed by cytisine, whereas compounds 5 and 6 represented the first example of the addition products of cytisine and 5,6-dihydroxy-4-hexanolide. Their structures were elucidated by comprehensive spectroscopic data analysis and quantum chemistry calculations including GIAO 13C{1H} NMR and ECD calculation, combined with single-crystal X-ray diffraction analysis. Biologically, compound 3 displayed significant anti-tobacco mosaic virus activity compared with the positive control ningnanmycin.

Three New Pregnanes Isolated from the Cynanchum auriculatum.

Three new compounds named cynansteroid A (1), cynansteroid B (2) and cynansteroid C (3), together with nine known C21 -steroidal pregnane sapogenins (4-12) were isolated from the hydrolytic extract of the roots of Cynanchum auriculatum. The structures of cynansteroid A-C (1-3) were ascertained via the detailed analysis of the HR-ESI-MS, 1D and 2D NMR, and the calculated and experimental ECD data of cynansteroid B (2). Compound 11 displayed moderate inhibitory activity toward Verticillium dahliae Kleb (IC50 =37.15 µM), furthermore, compounds 11 and 12 showed significant inhibitory activity against Phomopsis sp. (IC50 =16.49 µM and 17.62 µM, respectively).

Oreocharioside A-G, new acylated C-glycosylflavones from Oreocharis auricula (Gesneriaceae).

Seven new acylated C-glycosylflavones, oreocharioside A-G, together with two known compounds were isolated from the whole plant of Oreocharis auricula. Their structures were characterized by the comprehensive analysis of their NMR, IR, UV, CD spectra and HRESIMS data. All the new compounds were evaluated for the antioxidant and anti-inflammatory activities. The results showed that compounds 1 and 2 had significant DPPH and ABTS radical scavenging activities, with the IC50 values of 0.32-3.20 µg/mL. Compounds 2 and 3 exhibited the higher potency among all the new compounds in reducing TNF-α production.

Thermlanseedlines A-G, seven thermopsine-based alkaloids with antiviral and insecticidal activities from the seeds of Thermopsis lanceolata R. Br.

Seven undescribed thermopsine-based alkaloids (1-7), including one undescribed biogenetically related intermediate (7), were isolated from the seeds of Thermopsis lanceolata R. Br. Compound 1 possessed a 6/6-6 tricyclic skeleton, while compounds 2-6 represented three rare dimerization patterns constructed by quinolizidine alkaloids. Their structures were elucidated by comprehensive spectroscopic data analysis as well as ECD calculations. Biologically, compound 6 displayed significant anti-Tomato spotted wilt virus (TSWV) activity compared with the positive control ningnanmycin. Moreover, compound 1 exhibited good insecticidal activity against Aphis fabae with LC50 value of 25.2 mg/L.

Two new cytisine-type alkaloids from the seeds of Thermopsis lanceolata.

Two new (1 and 2) cytisine-type alkaloids that were chemically inseparable isomers (present in a 1:1 ratio) were identified from the seeds of Thermopsis lanceolata R. Br. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, HRESIMS) and ECD calculation. Compound 1 displayed significant anti-tobacco mosaic virus (TMV) activity, while compounds 1 and 2 displayed moderate insecticidal activities against Aphis fabae with LC50 value of 43.15 and 46.47 mg/L, respectively.

Chemical constituents from the flowers of Hypericum monogynum L. with COX-2 inhibitory activity.

Hypericum monogynum L. (Hypericaceae) has been used as a folk Chinese medicine for the treatment of inflammatory related diseases. Cyclooxygenase-2 (COX-2) is a crucial target for the development of agents to treat inflammation. To search for anti-inflammatory compounds from traditional Chinese medicines, a chemical constituent study along with COX-2 inhibitory activity analysis was performed for this plant. In this study, sixteen chemical monomers, including three undescribed oxidative degradation polycyclic polyprenylated acylphloroglucinols (PPAPs, hypemoins C-E), two undescribed PPAPs (hypemoins A and B), and 11 known compounds, were identified from the flowers of H. monogynum. Their structures were characterized by HRESIMS, NMR techniques, ECD, and single crystal X-ray diffraction. Four flavonoid derivatives showed remarkable COX-2 inhibitory activities, with IC50 values ranging from 0.220 ± 0.006 to 1.655 ± 0.098 µM. Among these compounds, the possible recognition mechanism between quercetin 3-(6″-O-caffeoyl)-ß-3-D-galactoside and COX-2 was predicted by molecular docking analysis. Moreover, the multidrug resistance reversal activities for the selected compounds were evaluated.

Hypermoins A-D: Rearranged Nor-Polyprenylated Acylphloroglucinols from the Flowers of Hypericum monogynum.

Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.

Hymoins A-D: Two Pairs of Polyprenylated Acylphloroglucinols from Hypericum monogynum and Their Light-Induced Transformation.

Hymoins A-D (1-4), two pairs of light-induced transformative polyprenylated acylphloroglucinols with an unprecedented pentacyclic skeleton, were isolated from the flowers of Hypericum monogynum. The first decarbonylative ring contraction of complex natural products was investigated by light irradiation. Their structures were elucidated by nuclear magnetic resonance analysis, X-ray crystallography, and electronic circular dichroism calculations. In addition, compound 3 showed moderate inhibition efficacy of the platelet-activating-factor-induced aggregation of rabbit platelets.

Anti-tobacco mosaic virus (TMV) activity of chemical constituents from the seeds of Sophora tonkinensis.

Two new compounds, including one new arylbenzofuran (1) and one new pterocarpanoid (2), along with nine known ones, were isolated from the seeds of Sophora tonkinensis. The structures of the new compounds were elucidated based on a comprehensive spectroscopic data analysis. Compounds 2 and 3 exhibited good anti-tobacco mosaic virus (TMV) activities with the protective inhibition rate of 69.62% and 68.72% respectively, at concentration of 100 µg/ml.

Polycyclic polyprenylated acylphloroglucinol derivatives with neuroprotective effects from Hypericum monogynum.

A new polycyclic polyprenylated acylphloroglucinol (PPAP), hypermonin C (1), along with nine known PPAPs (2-10) were obtained from the leaves and twigs of Hypericum monogynum. The structures of the isolates were determined on the basis of extensive spectroscopic analysis. The neuroprotective effects of the isolates against several chemical-induced injuries in SH-SY5Y and PC12 cells were assessed, and most of the compounds exhibited significant protective effects at 10 µg/ml. Especially, three compounds (1, 3, and 7) showed excellent neuroprotective activity with a cell viability of 92.4% ∼ 95.8% in KCl-induced SH-SY5Y cell injury. Their preliminary structure-activity relationship was also discussed and the configuration of substituent in furohyperforin may be critical for the neuroprotective activity of PPAP derivatives.

Two new seco-polycyclic polyprenylated acylphloroglucinol from Hypericum sampsonii.

Hypsampsone A (1) and hyperhexanone F (2), two novel seco-polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum sampsonii. Hypsampsone A (1) features the first spirocyclic system fused with 5/6/5/5 tetracyclic skeleton. Hyperhexanone F (2) represents the second novel 1,2-seco-bicyclo[3.3.1]-PPAP skeleton. Their structures were established by extensive spectroscopic analysis, computer-assisted structure elucidation software, and calculated electronic circular dichroism spectra. A plausible biogenetic pathway of 1 was also proposed. Compounds 1 and 2 showed moderate multidrug resistance reversal activity to adriamycin (ADR) resistant cancer cell lines, HepG2/ADR and MCF-7/ADR, with the fold-reversals ranging from 16 to 38 at noncytotoxic concentration of 10 µM.

Hyperfols A and B: Two Highly Modified Polycyclic Polyprenylated Acylphloroglucinols from Hypericum perforatum.

Two novel polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperfols A (1) and B (2), and two known biosynthetically related precursors (3 and 4) were isolated from Hypericum perforatum. Compound 1 possesses an unprecedented 2,3-seco-PPAP with a fused 5/5/9/5 tetracyclic skeleton, and 2 features a 30-norPPAP. Their structures were established by spectroscopic analysis, computer-assisted structure elucidation software, and electronic circular dichroism calculations. Moreover, compounds 1 and 4 exhibit significant cytotoxicity against human erythroleukemia cells by inducing cell apoptosis.

Design, synthesis, and cytotoxic activities of novel hybrids of parthenolide and thiazolidinedione via click chemistry.

A series of novel parthenolide-thiazolidinedione hybrids have been synthesized via a click chemistry-mediated coupling between parthenolide and thiazolidinedione, and evaluated for their cytotoxic activities. The results indicated that all the hybrids showed moderate cytotoxic effects on human cancer cell lines, including human erythroleukemia cell line (HEL), prostate (PC3), and breast (MDA-MB-231) by MTT assay. In particular, compound VI-6 exhibited the best cytotoxic activities against the MDA-MB-231 cells with IC50 value of 2.07 µM, which was about eight times more active than that of the original compound (PTL). These interesting results might be used to develop novel lead scaffolds for potential anticancer agents.

Cytotoxic phenolic constituents from Hypericum japonicum.

Nine undescribed compounds, including five xanthone derivatives, two flavonoids, one 2-pyrone derivative, and one undescribed naturally occurring compound, along with 30 known phenolic compounds, were isolated from Hypericum japonicum. In addition, hyperjaponols A and B were identified as racemates. The structures and absolute configurations of the undescribed compounds were determined by comprehensive MS, NMR spectroscopy, and electronic circular dichroism (ECD) calculations. The cytotoxic effects of the isolated compounds on two human tumour cell lines (HEL and MDA-MB-231) were evaluated by the MTT assay. Eighteen compounds showed good inhibitory activities against the HEL cell line, with IC50 values of 3.53-18.7 µM, while nine compounds exhibited moderate cytotoxicity against the MDA-MB-231 cancer cell line, with IC50 values ranging from 4.92 to 10.75 µM. Their preliminary structure-activity relationship of the isolated compounds was also discussed.