Bioactivity and structure-activity relationship of cinnamic acid derivatives and its heteroaromatic ring analogues as potential high-efficient acaricides against Psoroptes cuniculi.

A series of cinnamic acid derivatives and its heteroaromatic ring analogues were synthesized and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. Among them, eight compounds showed the higher activity with median lethal concentrations (LC50) of 0.36-1.07mM (60.4-192.1µg/mL) and great potential for the development of novel acaricidal agent. Compound 40 showed both the lowest LC50 value of 0.36mM (60.4µg/mL) and the smallest median lethal time (LT50) of 2.6h at 4.5mM, comparable with ivermectin [LC50=0.28mM (247.4µg/mL), LT50=8.9h], an acaricidal drug standard. SAR analysis showed that the carbonyl group is crucial for the activity. The type and chain length of the alkoxy in the ester moiety and the steric hindrance near the ester group significantly influence the activity. The esters were more active than the corresponding thiol esters, amides, ketones or acids. Replacement of the phenyl group of cinnamic esters with α-pyridyl or α-furanyl significantly increase the activity. Thus, a series of cinnamic esters and its heteroaromatic ring analogues with excellent acaricidal activity emerged.

[LncRNA MALAT1 Modulates the Immunoreaction of Rats with Lipopolysaccharide-induced Sepsis by Targeting the miR-146a/NF-κB P65 Pathway].

OBJECTIVE: To determine the regulatory and molecular mechanism of lncRNA MALAT1 in response to sepsis induced by lipopolysaccharide (LPS) in rats. METHODS: The expressions of lncRNA MALAT1 and miR-146a in U937 cells and peripheral blood samples of the rats with and without LPS-induced sepsis were detected using quantitative real-time reverse transcription PCR (qRT-PCR). The relationship between lncRNA MALAT1 and miR-146a was affirmed through luciferase assay. The expressions of p-P65, P65, TNF-α and iNOS were tested by Western blot. The expressions of TNF-α and iNOS in the lung tissues of the rats were measured by immunohistochemistry. RESULTS: The rats with LPS-induced sepsis had higher expressions of lncRNA MALAT1 in U937 cells than those without sepsis (P<0.001). In comparison with scramble, si-MALAT1 attenuated the expression of lncRNA MALAT1 and increased the expression of miR-146a (P<0.001). MiR-146a was the target of lncRNA MALAT1. si-MALAT1 decreased the p-P65/P65 ratio and and the expressions of TNF-α and iNOS in the rats with LPS-induced sepsis. In contrast, miR-146a inhibitor increased p-P65/P65 ratio and the expressions of TNF-α and iNOS in the rats with LPS-induced septis (P<0.001). Co-transfection with si-MALAT1 attenuated the elevated level of p-P65/P65 ratio and expressions of TNF-α and iNOS resulting from miR-146a inhibitor (P<0.001). LPS and scramble decreased the expression of miR-146a and increased the p-P65/P65 ratio compared with the healthy controls (P<0.01). Compared with scramble, si-MALAT1 increased the expression of miR-146a and attenuated the p-P65/P65 ratio (P<0.01). Higher numbers of TNF-α and iNOS positive cells were found in those with LPS-induced sepsis and those with scramble interventions (P<0.001). Compared with scramble, si-MALAT1 reduced the number of TNF-α and iNOS positive cells (P<0.01). CONCLUSIONS: LncRNA MALAT1 modulates the immunoreaction of rats with LPS -induced sepsis by targeting miR-146a/NF-κB P65.

Cytotoxic activity, apoptosis induction and structure-activity relationship of 8-OR-2-aryl-3,4-dihydroisoquinolin-2-ium salts as promising anticancer agents.

As our continuing research, a series of 2-aryl-8-OR-3,4-dihydroisoquinolin-2-ium bromides were evaluated for cytotoxic activity on cancer cells and apoptosis induction in the present study. SAR was derived also. Among them, 23 compounds showed the higher cytotoxicity on MKN-45 cells with IC50 values of 1.99-11.3µM than a standard anticancer drug cis-platinum (IC50=11.4µM) or their natural model compound chelerythrine (IC50=12.7µM); 16 compounds possessed the medium to high activity on NB4 cells with IC50 values of 1.67-4.62µM. SAR analysis showed that both substitution patterns of the N-aromatic ring and the type of 8-OR significantly impact the activity. AO/EB staining and flow cytometry analysis with Annexin V/PI double staining showed that the compounds were able to induce apoptosis in a concentration-dependent manner. The results above suggested that the title compounds are a class of promising compounds for the development of new anti-cancer drugs.

Synthesis of 2-aryl-3,4-dihydroisoquinolin-2-ium bromides and their in vitro acaricidal activity against Psoroptes cuniculi.

By employing sanguinarine, a natural active quaternary isoquinoline alkaloid, as a model molecule, a series of structurally simple quaternary 2-aryl-3,4-dihydroisoquinolin-2-ium compounds were designed and synthesized and evaluated for in vitro acaricidal activity against P. cuniculi. A new approach towards the title compounds was developed with isochroman as starting material. The results showed that 22 of 24 tested compounds displayed the activity in varying degrees at 0.4 mg/mL. Fourteen compounds were significantly more effective than ivermectin, a standard acaricide, and 6-methoxy dihydrosanguinarine, a derivative of sanguinarine (p<0.05). And their comprehensive relative activity was 1.4 to 16.5 times than that of ivermectin and 1.5 to 18.8 times than that of 6-methoxy dihydrosanguinarine. The structure-activity relationship indicated that the introduction of a substituent to N-benzene ring, especially halogen atom and trifluoromethyl group, led to great improvement of the activity. The position of fluorine atom, methyl group and hydroxyl group made very significant effects on the activity. It was concluded that 2-aryl-3,4-dihydroisoquinolin-2-iums are very promising candidates for the development of new isoquinoline acaricidal agents.

2-(Substituted phenyl)-3,4-dihydroisoquinolin-2-iums as novel antifungal lead compounds: biological evaluation and structure-activity relationships.

The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs). In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 µg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2-12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88-19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

Structural modification of sanguinarine and chelerythrine and their in vitro acaricidal activity against Psoroptes cuniculi.

Sanguinarine (1) and chelerythrine (2) are two quaternary benzo[c]phenanthridine alkaloids (QBAs). Eighteen derivatives of 1 and 2 were synthesized by modification of C=N(+) bond and evaluated for their in vitro acaricidal activity against Psoroptes cuniculi, a mange mite. A new method was developed to prepare 6-alkoxy dihydro derivatives of 1 and 2 (1a-e, 2a-e). Among all the compounds, only 6-alkoxy dihydrosanguinarines (1a-e) showed significant acaricidal activity at 5.0 mg/mL and 1a possessed the strongest activity (50% lethal concentrations (LC(50))=339.70±0.75 mg/L, 50% lethal time (LT(50))=6.53±0.04 h), comparable with a standard drug ivermectin (LC(50)=168.19±11.79 mg/L, LT(50)=16.54±0.11 h). The iminium moiety in 1 and 2 was proven to be the determinant for their acaricidal properties. 6-Alkoxy dihydro derivatives (1a-e, 2a-e) were prodrugs of 1 and 2. Compared with 7,8-dimethoxy groups, 7,8-methylenedioxy group was able to significantly improve the bioactivity. The present results suggested that QBAs are promising candidates or lead compounds for the development of new isoquinoline acaricidal agents.

Isolation, identification and antimicrobial activities of two secondary metabolites of Talaromyces verruculosus.

From the ethyl acetate extract of the culture broth of Talaromyces verruculosus, a rhizosphere fungus of Stellera chamaejasme L., (-)-8-hydroxy-3-(4-hydroxypentyl)-3,4-dihydroisocoumarin (1) and (E)-3-(2,5-dioxo-3-(propan-2-ylidene)pyrrolidin-1-yl)acrylic acid (2) were isolated and evaluated for their antimicrobial activities. Their structures were elucidated by UV, IR, MS, 1H-NMR, 13C-NMR and 2D NMR spectra. Compound 1 exhibited the significant activities in vitro against two strains of bacteria and four strains of fungi. Compound 2 gave slight activities on the fungi at 100 µg mL(-1), but no activities on the bacteria. Compound 1 should be considered as a new lead or model compound to develop new isocoumarin antimicrobial agents.

In vitro antifungal activity of sanguinarine and chelerythrine derivatives against phytopathogenic fungi.

In order to understand the antifungal activity of some derivatives of sanguinarine (S) and chelerythrine (C) and their structure-activity relationships, sixteen derivatives of S and C were prepared and evaluated for in vitro antifungal activity against seven phytopathogenic fungi by the mycelial growth rate method. The results showed that S, C and their 6-alkoxy dihydro derivatives S1-S4, C1-C4 and 6-cyanodihydro derivatives S5, C5 showed significant antifungal activity at 100 µg/mL against all the tested fungi. For most tested fungi, the median effective concentrations of S, S1, C and C1 were in a range of 14-50 µg/mL. The structure-activity relationship showed that the C=N+ moiety was the determinant for the antifungal activity of S and C. S1-S5 and C1-C5 could be considered as the precursors of S and C, respectively. Thus, the present results strongly suggested that S and C or their derivatives S1-S5 and C1-C5 should be considered as good lead compounds or model molecules to develop new anti-phytopathogenic fungal agents. can't login to work station for 2hrs--took 2 hrs vacation

New 7-Chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-iums as Promising Fungicide Candidates: Design, Synthesis, and Bioactivity.

As our further research, a series of new 7-chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-iums were designed and synthesized. Twelve compounds were found with excellent inhibition activity in vitro on three to five out of six phytopathogenic fungi, superior to standard drugs thiabendazole and/or azoxystrobin. Especially, 18 displayed the highest activity against three out of the fungi and the highest comprehensive activity for all of the fungi. The test in vivo revealed that 18 at 50 µg/mL was able to completely control Physalospora piricola infections in apples over 8 days. Scanning/transmission electron microscopic observations found that 18 could damage the hyphal integrity and cell membrane structure of P. piricola. The safety evaluation showed that 18 had no effect on the germination rate of cowpea seed at ≤200 µg/mL. The SAR revealed that the combination of 7-Cl and 2'- or 4'-alkyl is conducive to improvement of the activity. Thus, 7-chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-ium is a promising antifungal lead scaffold.

(E)-3-[2,5-Dioxo-3-(propan-2-yl-idene)pyrrolidin-1-yl]acrylic acid.

The title compound, C(10)H(11)NO(4), was extracted from a culture broth of Penicillium verruculosum YL-52. The mol-ecular structure is essentially planar, with an r.m.s. deviation of 0.01342 (2) Šfor the non-H atoms. In the crystal structure, adjacent mol-ecules are connected into a centrosymmetric dimer through a pair of O-H⋯O hydrogen bonds. The dimers are further extended into a chain by weak C-H⋯O hydrogen bonds.

Simple Analogues of Quaternary Benzo[c]phenanthridine Alkaloids: Discovery of a Novel Antifungal 2-Phenylphthalazin-2-ium Scaffold with Excellent Potency against Phytopathogenic Fungi.

Inspired by sanguinarine and chelerythrine, a novel antifungal 2-phenylphthalazin-2-ium scaffold as a simple analogue was designed. Most of the 30 compounds showed excellent inhibition activity against almost all eight phytopathogenic fungi, far superior to sanguinarine and chelerythrine. A third of the compounds were more active than azoxystrobin in most cases. Compounds 26 and 27 showed the highest total activity against all the fungi with EC50 means of ca. 4.6 µg/mL. Fusarium solani showed the highest susceptibility with an EC50 mean of 3.62 µg/mL to 19 compounds. A concentration of 25.0 µg/mL 27 can fully control the Colletotrichum gloeosporioides infection in apples over 9 days. Electron microscopic observations showed that 27 was able to damage the structures of the hypha and cell membrane. The structure-activity relationship showed that the presence of electron-withdrawing groups on the C-ring increases the activity against most of the fungi. Thus, 2-phenylphthalazin-2-ium compounds represent promising leads for the development of novel fungicides.

Further studies on the chemical constituents of Chinese folk medicine Gentiana apiata N.E. Br.

One new secoiridoid glycoside with conjugated diene, named 3-epi-swertiajaposide C (1), was isolated from the whole plants of Gentiana apiata N.E. Br., together with 11 known compounds, 7-deoxyloganic acid (2), isoorientin (3), gentiopicroside (4), silybin B (5), swertiamarin (6), asystasioside A (7), 6'-O-beta-D-glucopyranosylgentiopicroside (8), umbelliferone (9), oleanolic acid (10), kaempferol (11), and beta-sitosterol (12). The structure of the new compound (1) was elucidated on the basis of spectroscopic evidence including UV, IR, MS, NMR, HMBC, HMQC, and NOESY. Compounds 1, 2, 5, 6, 8, 9, and 11 were found in this plant for the first time. Moreover, silybin B (5) was isolated from the other plants besides Silybum marianum (L.) Gaertn for the first time by the present study.

Structural modification of sanguinarine and chelerythrine and their antibacterial activity.

In this study, five derivatives of sanguinarine (1) and chelerythrine (2) were prepared, with 1 and 2 as starting materials, by reduction, oxidation and nucleophilic addition to the iminium bond C=N+. The structures of all compounds were elucidated on account of their MS, ¹H-NMR and ¹³C-NMR data. The antibacterial activities of all compounds were screened, using Staphylococcus aureus, Escherichia coli, Aeromonas hydrophila and Pasteurella multocida as test bacteria. The minimum bacteriostatic concentration and minimum bactericidal concentration of the active compounds were determined by the turbidity method. The structure-activity relationships of 1 and 2 were discussed. The results showed that 1, 2 and their pseudoalcoholates were found to be potent inhibitors to S. aureus, E. coli and A. hydrophila, while the other derivatives were found to be inactive. The pseudoalcoholates might be the prodrugs of 1 and 2. The iminium bond in the molecules of 1 or 2 was the determinant for antibacterial activity, and the substituents at the 7 and 8 positions influenced the antibacterial activities of 1 and 2 against different bacteria.