Development of natural perfume as potential fungicide candidates: construction and biological evaluation of vanillin analogs bearing the 1,3,4-oxadiazole/1,3-thiazolidin-4-one fragments.

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 µg/ml) and 7a (38.15 µg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 µg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 µg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.

S100a9 inhibits Atg9a transcription and participates in suppression of autophagy in cardiomyocytes induced by ß1-adrenoceptor autoantibodies.

BACKGROUND: Cardiomyocyte death induced by autophagy inhibition is an important cause of cardiac dysfunction. In-depth exploration of its mechanism may help to improve cardiac dysfunction. In our previous study, we found that ß1-adrenergic receptor autoantibodies (ß1-AAs) induced a decrease in myocardial autophagy and caused cardiomyocyte death, thus resulting in cardiac dysfunction. Through tandem mass tag (TMT)-based quantitative proteomics, autophagy-related S100a9 protein was found to be significantly upregulated in the myocardial tissue of actively immunized mice. However, whether S100a9 affects the cardiac function in the presence of ß1-AAs through autophagy and the specific mechanism are currently unclear. METHODS: In this study, the active immunity method was used to establish a ß1-AA-induced mouse cardiac dysfunction model, and RT-PCR and western blot were used to detect changes in gene and protein expression in cardiomyocytes. We used siRNA to knockdown S100a9 in cardiomyocytes. An autophagy PCR array was performed to screen differentially expressed autophagy-related genes in cells transfected with S100a9 siRNA and negative control siRNA. Cytoplasmic nuclear separation, co-immunoprecipitation (Co-IP), and immunofluorescence were used to detect the binding of S100a9 and hypoxia inducible factor-1α (HIF-1α). Finally, AAV9-S100a9-RNAi was injected into mice via the tail vein to knockdown S100a9 in cardiomyocytes. Cardiac function was detected via ultrasonography. RESULTS: The results showed that ß1-AAs induced S100a9 expression. The PCR array indicated that Atg9a changed significantly in S100a9siRNA cells and that ß1-AAs increased the binding of S100a9 and HIF-1α in cytoplasm. Knockdown of S100a9 significantly improved autophagy levels and cardiac dysfunction. CONCLUSION: Our research showed that ß1-AAs increased S100a9 expression in cardiomyocytes and that S100a9 interacted with HIF-1α, which prevented HIF-1α from entering the nucleus normally, thus inhibiting the transcription of Atg9a. This resulted in autophagy inhibition and cardiac dysfunction.

miR-339-3p promotes AT1-AA-induced vascular inflammation by upregulating NFATc3 protein expression in vascular smooth muscle cells.

Vascular inflammation induced by angiotensin II-1 receptor autoantibody (AT1-AA) is involved in the occurrence and development of various cardiovascular diseases. miR-339-3p is closely related to the degree of vasodilation of aortic aneurysm and is also involved in the occurrence and development of acute pancreatitis. However, it is still unclear whether miR-339-3p influences AT1-AA-induced vascular inflammation. In this study, the role and mechanism of miR-339-3p in AT1-AA-induced vascular inflammation are studied. RT-PCR detection shows that the miR-339-3p levels in the thoracic aorta and serum exosomes of AT1-AA-positive rats are significantly increased. The miRwalk database predicts the mRNAs that miR-339-3p can bind to their 5'UTR. Subsequently, it is found that the number of genes contained in the T cell receptor pathway is high through KEGG analysis, and NFATc3 among them can promote the secretion of various inflammatory cytokines. AT1-AA-induced upregulation of miR-339-3p expression in vascular smooth muscle cells (VSMCs) can lead to a significant increase in NFATc3 protein level and promote vascular inflammation. Inhibition of miR-339-3p with antagomir-339-3p can significantly reverse AT1-AA-induced high expressions of IL-6, IL-1ß and TNF-α proteins in rat thoracic aorta and VSMCs. That is, AT1-AA can upregulate the expression of miR-339-3p in VSMCs, and the increased miR-339-3p targets the 5'UTR of NFATc3 mRNA to increase the protein level of NFATc3, thereby aggravating the occurrence of vascular inflammation. These findings provide new experimental evidence for the involvement of miRNAs in regulating vascular inflammatory diseases.

Synthesis and in vitro antifungal activity of new Michael-type amino derivatives of xanthatin, a natural sesquiterpene lactone from Xanthium strumarium L.

Structural optimization using plant secondary metabolites as templates is one of the important approach to discover pesticide molecules with novel skeletons. Xanthatin, a natural sesquiterpene lactone isolated from the Xanthium plants (Family: Compositae), exhibits important biological properties. In this work, a series of Michael-type amino derivatives were prepared from xanthatin and their structures were characterized by 1H NMR, 13C NMR and HR-MS, and their antifungal activities against several phytopathogenic fungi were evaluated according to the spore germination method and mycelium growth rate method in vitro. The results illustrated that compounds 2g (IC50 = 78.91 µg/mL) and 2o (IC50 = 64.51 µg/mL) exhibited more promising inhibition activity against spores of F. solani than precursor xanthatin, compounds 2g, 2l, and 2r exhibited remarkable antifungal effect on C. mandshurica with the average inhibition rates (AIRs) >90%, whereas the AIR of xanthatin was only 59.34%. Meanwhile, the preliminary structure-activity relationships suggested that the amino containing 2-methoxyethyl or 4-chlorophenylmethyl group appended in the C-13 position of xanthatin could yield potential compounds against fungal spores, and the exocyclic double bond of xanthatin is essential to maintain its mycelial growth inhibitory activity. Therefore, the aforementioned findings indicate that partial xanthatin amino-derivatives could be considered for further exploration as the potential lead structures toward development of the new environmentally friendly fungicidal candidates for sustainable crop protection.

Semisynthesis and insecticidal bioactivities of benzoxazole and benzoxazolone derivatives of honokiol, a naturally occurring neolignan derived from Magnolia officinalis.

Honokiol, a natural bioactive neolignan isolated from the bark and leaf of Magnolia officinalis and Magnolia obovata, exhibits many important biological properties. In continuation of our interest in discovery of the agrochemicals derived from the natural sources, thirty-seven new 8/8'-alkylthiol-benzoxazole and N-alkyl/sulfonyl-benzoxazolone derivatives of honokiol were prepared and their insecticidal activities were evaluated against the larvae of Mythimna separata Walker and Plutella xylostella Linnaeus. The results showed that eleven derivatives exhibited potent insecticidal activity against M. separata when compared with the positive control. Particularly, compound 5h displayed the most promising insecticidal activity against M. separata with the final mortality rate (FMR) of 58.6%. Meanwhile, compounds 7n (FMR = 65.3%), 7p (FMR = 61.5%), and 8c (FMR = 65.3%) demonstrated a greater insecticidal activity against P. xylostella than toosendanin, a well-known botanical insecticide. Additionally, the preliminary structure-activity relationships (SARs) were also discussed. This study indicates that these honokiol derivatives could be used as leads for the further derivation and development of the potential pesticide candidates for crop protection.

Semisynthesis and biological evaluation of some novel Mannich base derivatives derived from a natural lignan obovatol as potential antifungal agents.

Obovatol, a novel lignan isolated from the leaf and stem bark of Magnolia obovata Thunb exhibits many important biological activities. To discover natural-product-based potential fungicides with novel structural skeletons, a series of Mannich base derivatives were prepared by the C-4-aminomethylated modification of obovatol and all synthesized compounds were evaluated for antifungal activities in vitro against several phytopathogenic fungi using the spore germination method and the mycelium growth rate method. Furthermore, their structures were also characterized by 1H NMR, 13C NMR, and HR-MS, and compound 2k was further analyzed by single-crystal X-ray diffraction. Among all of the derivatives, compounds 2b (IC50 = 28.68 µg/mL) and 2g (IC50 = 16.90 µg/mL) demonstrated greater inhibition of Botrytis cinerea spore germination than two positive controls, hymexazol and difenoconazole. Compounds 2c, 2f, and 2g displayed potent mycelial growth inhibition of B. cinerea with an average inhibition rate (AIR) of >90% at a concentration of 100 µg/mL. Additionally, the structure-activity relationships (SARs) suggested that the introduction of a diethylamino, pyrrolyl, 1-methyl-piperazinyl or 1-ethyl-piperazinyl groups on the C-4 position of obovatol may be more likely to yield potential antifungal compounds than the introduction of 4-phenyl-piperazinyl or 4-phenyl-piperidinyl groups.

Natural product-based semisynthesis and biological evaluation of thiol/amino-Michael adducts of xanthatin derived from Xanthium strumarium as potential pesticidal agents.

Xanthatin, a natural sesquiterpene lactone, occurs as one of the major constituents of Xanthium plants (Compositae) and exhibits many important biological properties. To discover natural products-based pesticides, forty-nine Michael-type thiol/amino adducts of xanthatin were synthesized and characterized, while their pesticidal activities were investigated. Among them, compounds 2c, 2h, 2i, and 2t exhibited more potent antifungal activity against Botrytis cinerea (IC50 = 0.96, 0.38, 6.33, and 7.21 µg/mL, respectively) than xanthatin and the two commercial fungicides. Compounds 2t and 2u displayed broad-spectrum and excellent antifungal effects against all tested phytopathogenic fungi, while their IC50 values ranged from 7.21 to 75.88 µg/mL. Compounds 2a, 2f, 2l, 2m, 2v, 7c, 7e, 7h, 7i, and 7j showed moderate larvicidal activity against Plutella xylostella Linnaeus. Furthermore, compounds 2b, 7g, and 7h demonstrated significant ovicidal activity against P. xylostella with the LC50 values of 14.04, 10.00, and 11.95 mg/L, respectively. These findings suggest that thiol/amino appended in the C-13 position of xanthatin may improve antifungal and ovicidal activities for the derivatives. It was also noticed that the exocyclic double bond of xanthatin is crucial for its larvicidal activity. This work also provides some important hints for further design, synthesis, and structural modification of the xanthanolides sesquiterpene lactones toward development of the new environmentally friendly pesticides for sustainable agricultural production.

Synthesis of benzoxazole derivatives of honokiol as insecticidal agents against Mythimna separata Walker.

A series of novel benzoxazole compounds derived from a naturally occurring neolignan honokiol were prepared. Their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm (Mythimna separata Walker) in vivo. Most of the tested derivatives exhibited more potential insecticidal activity than their precursor honokiol at the concentration of 1mg/mL. Especially compound 6e, containing 4-acetyloxyphenyl groups at the C8 and C8' positions, displayed the most potent insecticidal activity with the final mortality rate of 62.1%.

Insight into reduction of obacunone, and their ester derivatives as insecticidal agents against Mythimna separata Walker.

Here we have prepared a series of ester compounds of obacunone, a naturally occurring limonoid, isolated from plants such as Citrus and Dictamnus angustifolius. Their insecticidal activity was evaluated at 1 mg/mL against the pre-third-instar larvae of oriental armyworm (Mythimna separata Walker), a typical lepidopteran pest. When obacunone reacted with NaBH4, the ratio of two reduction products, C7α-hydroxyobacunone (2) and C7ß-hydroxyobacunone (3), was related to the reaction mixing solvents. C7α-Propionyloxybacunone (4b) and C7ß-(n)heptanoyloxybacunone (5g) exhibited the more promising insecticidal activity than their precursor obacunone and toosendanin.

Semisynthesis and insecticidal activity of arylmethylamine derivatives of the neolignan honokiol against Mythimna separata Walker.

A series of novel arylmethylamine derivatives of honokiol (5a-m) was prepared. Their insecticidal activity was tested against the pre-third-instar larvae of the oriental armyworm (Mythimna separata Walker), a typical lepidopteran pest. Compounds 5a, 5b, 5e, 5h, and 5k exhibited insecticidal activity equal to, or higher than, that of the positive control toosendanin.

Synthesis and insecticidal activity of new deoxypodophyllotoxin derivatives modified in the D-ring.

In continuation of our program aimed at the discovery of new natural-product-based insecticidal agents, twenty-six deoxypodophyllotoxin derivatives modified in the D-ring were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. The configuration of three compounds 3, 4, and IIIi was unambiguously determined by single-crystal X-ray diffraction. It demonstrated that aminolysis of deoxypodophyllotoxin in the presence of pyrrolidine and piperidine could result in complete inversion of the configuration of the carbonyl group at its C-2 position. Five compounds IIa, IIi-k, and IIIh showed the equal or higher insecticidal activity than toosendanin. Especially IIj displayed the most potent insecticidal activity with the final mortality rate of 65.5%.

Synthesis and insecticidal activity of new oxime derivatives of podophyllotoxin-based phenazines against Mythimna separata Walker.

To discover new natural-product-based insecticidal agents, a series of novel oxime derivatives of podophyllotoxin-based phenazines modified in the C, D and E rings of podophyllotoxin were prepared and tested as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. The steric configuration of IIIc was unambiguously confirmed by single-crystal X-ray diffraction analysis. Compounds IIIa-d, and IIIi exhibited an equal or higher insecticidal activity than toosendanin.

Synthesis and insecticidal activity of novel hydrazone compounds derived from a naturally occurring lignan podophyllotoxin against Mythimna separata (Walker).

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, a series of novel hydrazone derivatives of podophyllotoxin, which is a naturally occurring aryltetralin lignan and isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum species, were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. Especially compounds 8i, 8j, 8t, and 8u showed the more potent insecticidal activity with the final mortality rates greater than 60%.

Synthesis of 4ß-acyloxypodophyllotoxin analogs modified in the C and E rings as insecticidal agents against Mythimna separata Walker.

To discover the new natural-product-based insecticidal agents, four series of sixty novel 4ß-acyloxypodophyllotoxin analogs modified in the C and E rings were prepared, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at the concentration of 1 mg/mL. It demonstrated that the position of the dioxo group on the E-ring of 4'-demethylepipodophyllotoxin was regioselectively controlled by the chlorine atom at its C-2' position when 2'-chloro-4'-demethylepipodophyllotoxin was oxidized by sodium periodate. Among all the derivatives, IIIi exhibited the best potent insecticidal activity with the final mortality rate of 63.3%. To alkylacyloxy series, the proper length of the side chain at the C-4 position of Ia-g, IIa-g and IIIa-g was important for their insecticidal activity.

Is the suppression of CD36 a promising way for atherosclerosis therapy?

Atherosclerosis is the main underlying pathology of many cardiovascular diseases and is marked by plaque formation in the artery wall. It has posed a serious threat to the health of people all over the world. CD36 acts as a significant regulator of lipid homeostasis, which is closely associated with the onset and progression of atherosclerosis and may be a new therapeutic target. The abnormal overexpression of CD36 facilitates lipid accumulation, foam cell formation, inflammation, endothelial apoptosis, and thrombosis. Numerous natural products and lipid-lowering agents are found to target the suppression of CD36 or inhibit the upregulation of CD36 to prevent and treat atherosclerosis. Here, the structure, expression regulation and function of CD36 in atherosclerosis and its related pharmacological therapies are reviewed. This review highlights the importance of drugs targeting CD36 suppression in the treatment and prevention of atherosclerosis, in order to develop new therapeutic strategies and potential anti-atherosclerotic drugs both preclinically and clinically.

Phenanthroimidazole-based thiobenzamide as an effective sensor for highly selective detection of mercury(II).

Based on highly selective and irreversible Hg(2+)-promoted desulfurization reaction, a new and simple phenanthroimidazole-type sensor was prepared and exhibited high selectivity towards Hg(2+) ion over other metal ions, accompanied by transformation of a weakly fluorescent thioamide moiety (colorless) to a highly fluorescent amide one (blue), with a 136-fold increase in fluorescent intensity in aqueous solution with a pH span 2.57-9.12.

Natural-product-based insecticidal agents 14. Semisynthesis and insecticidal activity of new piperine-based hydrazone derivatives against Mythimna separata Walker in vivo.

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, twenty-six new piperine-based hydrazone derivatives were synthesized from piperine, an alkaloid isolated from Piper nigrum Linn. The single-crystal structures of 6c, 6q and 6w were unambiguously confirmed by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo. Especially compounds 6b, 6i and 6r, the final mortality rates of which, at the concentration of 1 mg/mL, were 62.1%, 65.5% and 65.5%, respectively, exhibited more pronounced insecticidal activity compared to toosendanin at 1 mg/mL, a commercial botanical insecticide isolated from Melia azedarach. It suggested that introduction of the substituents at the C-2 position on the phenyl ring of the hydrazone derivatives was important for their insecticidal activity.

Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v.

Fluorescence 'on-off-on' chemosensor for sequential recognition of Fe(3+) and Hg(2+) in water based on tetraphenylethylene motif.

A novel selective and sensitive fluorescence 'on-off-on' probe based on tetraphenylethylene (TPE) motif for sequential recognition of Fe(3+) and Hg(2+) in water has been developed. Especially the complex 6-Fe(3+) could behave as a 'turn on' fluorescent sensor over a wide-range pH value for detection of Hg(2+). The selectivity of this complex for Hg(2+) over other heavy and transition metal ions is excellent, and its sensitivity for Hg(2+) is at 2 ppb in water.

Natural Sesquiterpene Lactone as Source of Discovery of Novel Fungicidal Candidates: Structural Modification and Antifungal Activity Evaluation of Xanthatin Derived from Xanthium strumarium L.

As part of our ongoing efforts to discover novel agricultural fungicidal candidates from natural sesquiterpene lactones, in the present work, sixty-three xanthatin-based derivatives containing a arylpyrazole, arylimine, thio-acylamino, oxime, oxime ether, or oxime ester moiety were synthesized. Their structures were well characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry, while the absolute configurations of compounds 5' and 6a were further determined by single-crystal X-ray diffraction. Meanwhile, the antifungal activities of the prepared compounds against several phytopathogenic fungi were investigated using the spore germination method and the mycelium growth rate method in vitro. The bioassay results illustrated that compounds 5, 5', and 15 exhibited excellent inhibitory activity against the tested fungal spores and displayed remarkable inhibitory effects on fungal mycelia. Compounds 5 and 5' exhibited more potent inhibitory activity (IC50 = 1.1 and 24.8 µg/mL, respectively) against the spore of Botrytis cinerea than their precursor xanthatin (IC50 = 37.6 µg/mL), wherein the antifungal activity of compound 5 was 34-fold higher than that of xanthatin and 71-fold higher than that of the positive control, difenoconazole (IC50 = 78.5 µg/mL). Notably, compound 6'a also demonstrated broad-spectrum inhibitory activity against the four tested fungal spores. Meanwhile, compounds 2, 5, 8, and 15 showed prominent inhibitory activity against the mycelia of Cytospora mandshurica with the EC50 values of 2.3, 11.7, 11.1, and 3.0 µg/mL, respectively, whereas the EC50 value of xanthatin was 14.8 µg/mL. Additionally, compounds 5' and 15 exhibited good in vivo therapeutic and protective effects against B. cinerea with values of 55.4 and 62.8%, respectively. The preliminary structure-activity relationship analysis revealed that the introduction of oxime, oxime ether, or oxime ester structural fragment at the C-4 position of xanthatin or the introduction of a chlorine atom at the C-3 position of xanthatin might be significantly beneficial to antifungal activity. In conclusion, the comprehensive investigation indicated that partial xanthatin-based derivatives from this study could be considered for further exploration as potential lead structures toward developing novel fungicidal candidates for crop protection.