Synthesis and Antifungal Evaluation of Cinnamic Acid-Geraniol Hybrids as Potential Fungicides.

Cinnamic acid and geraniol are two well-known antifungal natural products and widely applied in food and cosmetics industries. To discover novel natural product-based fungicide candidates with more potent activity and good ecological compatibility for the management of plant diseases, a series of cinnamic acid-geraniol hybrids were prepared by means of molecular hybridization and their chemical structures were well confirmed by spectral analysis. The antifungal activities of the target compounds against three phytopathogenic fungi Fusarium graminearum, Gaeumannomycesgraminis (Sacc.) Arx et Oliver var. tritici (Sacc.) Walker, and Valsa mali were evaluated. Among them, compounds 5e and 5f showed the remarkable antifungal activity against G. graminis with the EC50 values of 82.719 and 91.828 µg/mL, respectively; while compounds 5f and 6b exhibited the obvious antifungal activity against V. mali. It suggested that compound 5f can be further optimized for the design of novel broad-spectrum fungicide molecules as the secondary lead compound. In addition, some interesting structure-antifungal activity relationships were obtained. This work will provide some reference and guidance for the further discovery of novel fungicide candidates based on cinnamic acid and geraniol.

Synthesis of hemostatic aerogel of TEMPO-oxidized cellulose nanofibers/collagen/chitosan and in vivo/vitro evaluation.

The treatment of internal hemorrhage remains challenging due to the current limited antibacterial capability, hemostatic efficacy, and biocompatibility of hemostatic materials. The TEMPO-oxidized cellulose nanofibers/collagen/chitosan (TCNF/COL/CS) hemostatic aerogel was developed in this work by physically encasing COL in a sandwich structure and electrostatically self-assembling polyanionic TCNF with polycationic CS. In vitro coagulation experiments revealed the favorable procoagulant properties of TCNF/COL/CS along with high adhesion to erythrocytes and platelets. TCNF/COL/CS significantly increased the hemostatic efficacy by 59.8 % and decreased blood loss by 62.2 % in the liver injury model when compared to Surgicel®, the most frequently used hemostatic material. Furthermore, it demonstrated outstanding biodegradability both in vitro and in vivo, and a substantial increase in resistance (96.8 % against E. coli and 95.4 % against S. aureus) compared to TCNF. The significant hemostatic and biodegradable characteristics of TCNF/COL/CS can be ascribed to its interconnected porous structure, increased porosity, and efficient water absorption, along with the synergistic effect of the three constituents. The TCNF/COL/CS aerogel shows significant potential to control internal bleeding. A novel plant-derived nanocellulose composite aerogel has been described here for the first time; it has outstanding antibacterial characteristics, higher biocompatibility, and outstanding hemostatic characteristics in vivo.

Highly efficient synthesis of enantioenriched vicinal halohydrins via Ir-catalyzed asymmetric hydrogenation using dynamic kinetic resolution.

A novel synthetic route was developed for the construction of chiral cis-vicinal halohydrins derivatives through Ir/f-phamidol-catalysed asymmetric hydrogenation of corresponding α-halogenated ketones with high yields (up to 99% yield), excellent diastereoselectivities (>20 : 1 dr), enantioselectivities (up to 99% ee), and high substrate catalyst ratio (S/C = 1000).

Dynamic Kinetic Resolution of ß-Cyano α-Ketoesters via Asymmetric Transfer Hydrogenation.

An efficient rhodium-catalyzed asymmetric transfer hydrogenation of ß-cyano α-ketoesters via dynamic kinetic resolution has been developed. Despite the challenge posed by multiple functional groups, the reaction proceeded smoothly under mild conditions, generating versatile synthons with two adjacent stereocenters in high yields with excellent enantio- and diastereoselectivities. Furthermore, the power of this strategy is highlighted by the scale-up reaction and the follow-up synthesis of cytoxazone and paclitaxel intermediates.

Synthesis, Anti-Oomycete and Anti-Fungal Activities of Anhydride Derivatives of Oleanolic Acid.

Oleanolic acid is a pentacyclic triterpenoid extracted and isolated from the fruit of plants in the Ligustrum lucidum Ait. in the family Oleaceae. To discover biorational natural product-based pesticides, a series of oleanolic acid derivatives containing anhydride active skeletons were prepared by ingeniously introducing an active acyloxy group at its C-28 carboxyl position, and their structures were well characterized by 1H NMR, 13C NMR, HRMS, and m.p.. The stereochemical configuration of compound 8e was confirmed using single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete and anti-fungal agents against two serious agricultural pests, Phytophthora capsici and Fusarium graminearum we assessed. Amongst evaluated compounds, 1) Compounds 8h and 8j displayed significant anti-oomycete against P. capsici, with EC50 values of 54.73 and 65.15 mg/L, respectively. 2) The target compounds have obvious selectivity, and their anti-oomycete activity is significantly better than their anti-fungal activity. 3) Interestingly, there are significant differences in the structure-activity relationship of different substituents or the same substituent at different positions anti-oomycete and anti-fungal against P. capsici and F. graminearum, respectively. The study provides an idea for further exploring the bioactivities of 28-acyloxyoleanolic acid derivatives, and develops the application of 28-acyloxyoleanolic acid derivatives containing anhydride in agriculture.

Synthesis of paeonol hydrazone derivatives and their anti-oomycete, anti-fungal, and nematicidal activities.

BACKGROUND: The natural product paeonol is a rich and sustainable natural bioresource, and its derivatives have various unique biological efficacy. As is well known, Schiff bases are a class of organic compounds with a wide range of biological activities, including anti-fungal, insecticidal, anti-viral, and nematicidal. RESULTS: To discover biorational natural product-based pesticides, nine intermediates (2-10), 12 sulfonylhydrazones (11a-11c, 12a-12c, 13a-13c, and 14a-14c) and 20 benzylidene hydrazones (18a-18r, 19a, and 20a) were synthesized by structural modification of paeonol, and their structures were characterized by proton nuclear magnetic resonance (1H NMR), carbon-13 (13C) NMR, and high-resolution mass spectrometry (HRMS). The stereochemical configurations of compounds 14a, 18d, and 18r were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete, anti-fungal, and nematicidal agents against three serious agricultural pests, Phytophthora capsici, Fusarium graminearum, and Heterodera glycines were evaluated. Among all tested compounds: (i) compound 7 exhibited promising anti-oomycete against Phytophthora capsici, with a half maximal effective concentration (EC50) value of 15.81 mg L-1; (ii) compounds 2, 7, 10, and 19a displayed promising anti-fungal against F. graminearum, with EC50 values of 12.22, 14.72, 23.39, and 33.10 mg L-1, respectively; (iii) ten compounds (12a-12c, 14c, 18g-18j, 18m, and 19a) showed significant nematicidal activity against H. glycines, with median lethal concentration (LC50) values all less than 30.00 mg L-1. Especially for compound 18g, its LC50 value is the smallest, at 12.65 mg L-1. CONCLUSION: The research results indicate that introducing nitro groups at the C5 position of paeonol, or introducing halogens at both C5 and C3 positions, can significantly enhance its biological activity against Phytophthora capsici, F. graminearum, and H. glycines. © 2024 Society of Chemical Industry.

Highly Enantioselective Hydrogenation of Unsymmetrical Benzophenones via Iridium-f-phamidol Catalysis.

A sequence of f-phamidol-based tetradentate phosphine ligands have been developed and successfully used in iridium-catalyzed enantioselective hydrogenation of benzophenones to deliver chiral benzhydrols in almost quantitative yields and with excellent enantioselectivities (up to >99% yield and up to >99% ee). Moreover, the catalytic system shows a broad substrate scope and functional group tolerance. The synthetic utilities of this methodology have been showcased by gram-scale experiments and the formal synthesis of levocetirizine.

Robust, scalable, and highly selective spirocyclic catalysts for industrial hydroformylation and isomerization-hydroformylation.

Hydroformylation (HF) or isomerization-hydroformylation (ISO-HF) represents the most direct and practical route for producing aldehydes on an industrial scale. To resolve the issues of low activity, low linear/branched (l/b) ratio, and low stability in HF and ISO-HF, we herein reported a class of spirocyclic diphosphites. Notably, the ligand termed O-SDPhite afforded excellent catalytic activity and regioselectivity for the HF of various olefins. Excellent l/b ratio and an unprecedented turnover number of up to 17,620,000 were achieved. O-SDPhite was also found to be effective in the regioselective ISO-HF of the industrially related cheap and abundant C4 Raffinates to n-valeraldehyde produced on a multimillion-ton scale. The reaction with O-SDPhite, superior to that of benchmark Biphephos, was continuously operated for 41 days and afforded an average 38.6 l/b ratio (31 days and 14.7 l/b ratio for Biphephos).

Design, synthesis, and anti-oomycete activity of 3-acyloxymaltol/ethyl maltol derivatives.

Twenty 3-acyloxymaltol/ethyl maltol derivatives (7a-j and 8a-j) were synthesized and evaluated in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of twenty derivatives, more than half of the compounds 7f, 7h, 8a-h and 8j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 22.23 mg/L), and the EC50 values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds 8c and 8f exhibited the best anti-oomycete activity against P. capsici with EC50 values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.

Nanowire-assisted electroporation via inducing cell destruction for inhibiting formation of VBNC bacteria: Comparison with chlorination.

The induction of viable but nonculturable (VBNC) bacteria with cellular integrity and low metabolic activity by chemical disinfection causes a significant underestimation of potential microbiological risks in drinking water. Herein, a physical Co3O4 nanowire-assisted electroporation (NW-EP) was developed to induce cell damage via the locally enhanced electric field over nanowire tips, potentially achieving effective inhibition of VBNC cells as compared with chemical chlorination (Cl2). NW-EP enabled over 5-log removal of culturable cell for various G+/G- bacteria under voltage of 1.0 V and hydraulic retention time of 180 s, and with ∼3-6 times lower energy consumption than Cl2. NW-EP also achieved much higher removals (∼84.6 % and 89.5 %) of viable Bacillus cereus (G+) and Acinetobacter schindleri (G-) via generating unrecoverable pores on cell wall and reversible/irreversible pores on cell membrane than Cl2 (∼28.6 % and 41.1 %) with insignificant cell damage. The residual VBNC bacteria with cell wall damage and membrane pore resealing exhibited gradual inactivation by osmotic stress, leading to ∼99.8 % cell inactivation after 24 h storage (∼59.4 % for Cl2). Characterizations of cell membrane integrity and cell morphology revealed that osmotic stress promoted cell membrane damage for the gradual inactivation of VBNC cells during storage. The excellent adaptability of NW-EP for controlling VBNC cells in DI, tap and lake waters suggested its promising application potentials for drinking water, such as design of an external device on household taps.

Synthesis of Novel 4-Acyloxy-2'-Bromo-6'-Chloropodophyllotoxin Derivatives Displaying Significant Insecticidal Activity Against Mythimna Separata.

In order to explore novel natural product-based insecticidal agent, two important intermediates (2 and 3) and 4-acyloxy-2'-bromo-6'-chloropodophyllotoxin derivatives (4 a-f and 5 a-f) were designed and prepared, and their structures were confirmed by 1H-NMR, 13C NMR, HRMS, ESI-MS, optical rotation and melting point (mp). The stereochemical configuration of compound 4 b was unambiguously confirmed by single-crystal X-ray diffraction. Moreover, we evaluated the insecticidal activity of target compounds 4 a-f and 5 a-f against a serious agricultural pest of Mythimna separata by using the leaf-dipping method. Among all tested compounds, compounds 4 d, 5 d and 5 f exhibited stronger insecticidal activity with a final mortality rate exceeding 60 %. Especially compound 5 d exhibited the best insecticidal activity, with a final mortality rate of 74.1 %. It has been proven that introducing bromine or chlorine atoms at the C-2', C-2' and C-6' positions of the E ring of podophyllotoxin can produce more potent compounds. In addition, the configuration of the C-4 position is important for insecticidal activity, and 4ß-configuration is optimal. This will pave the way for further design, structural modification, and development of derivatives of podophyllotoxin as insecticidal agents.

Effects of heterogeneous surface characteristics on hemocompatibility and cytocompatibility of bacterial nanocellulose.

The surface properties of cardiovascular biomaterials play a critical role in their biological responses. Although bacterial nanocellulose (BNC) materials have exhibited potential applications in cardiovascular implants, the impact of their surface characteristics on biocompatibility has rarely been studied. This study investigated the mechanism for the biocompatibility induced by the physicochemical properties of both sides of BNC. With greater wettability and smoothness, the upper BNC surface reduced protein adsorption by 25 % compared with the lower surface. This prolonged the plasma re-calcification time by 14 % in venous blood. Further, compared with the lower BNC surface, the upper BNC surface prolonged the activated partial thromboplastin time by 5 % and 4 % in arterial and venous blood, respectively. Moreover, the lower BNC surface with lesser rigidity, higher roughness, and sparser fiber structure promoted cell adhesion. The lower BNC surface enhanced the proliferation rate of L929 and HUVECs cells by 15 % and 13 %, respectively, compared with the upper BNC surface. With lesser stiffness, the lower BNC surface upregulated the expressions of CD31 and eNOS while down-regulating the ICAM-1 expression - This promoted the proliferation of HUVECs. The findings of this study will provide valuable insights into the design of blood contact materials and cardiovascular implants.

Design, synthesis and anti-oomycete activity of 2-acyloxyhinokitiol derivatives.

In order to explore novel natural product-based anti-oomycete agent, ten 2-acyloxyhinokitiol derivatives (5a-j) were designed and synthesised, and structurally confirmed by 1H NMR,13C NMR, HRMS, and melting point. The stereochemical configuration of compound 5f was unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we evaluated the target compounds 5a-j as anti-oomycete activity against a serious agricultural disease of Phytophthora capsici. Among the ten hinokitiol ester derivatives tested, four compounds 5d, 5g, 5h and 5j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 23.59 mg/L), and the EC50 values of 18.90, 20.62, 13.61 and 21.29 mg/L, respectively. Especially compound 5h exhibited the best anti-oomycete activity against P. capsici with EC50 value of 13.61 mg/L. Overall, the anti-oomycete activities of 2-acyloxyhinokitiol derivatives is higher than that of 2-sulfonyloxyhinokitiol derivatives. The results laid a good foundation for the subsequent synthesis of hinokitiol ester derivatives with significant anti-oomycete activity.

Chitosan particles embedded bacterial nanocellulose flat membrane for hemodialysis.

The development of bio-based hemodialysis membranes continues to be a challenge. Bacterial nanocellulose (BNC) membranes show potential in hemodialysis but can hardly retain beneficial proteins. Here, chitosan particles/bacterial nanocellulose (CSP/BNC) membranes were designed to efficiently remove uremic toxins and retain beneficial proteins. First, CSPs were synthesized in situ within a BNC membrane by ionic gelation following negative pressure impregnation. Subsequently, these membranes were thoroughly characterized. Compared with the BNC membrane, the pore volume and pore size of the 3 % CSP/BNC membrane decreased by 42.2 % and 32.1 %, respectively. The increased 22.2 times of Young's modulus and 88.9 % of tensile strength in the 3 % CSP/BNC membrane confirmed enhanced mechanical property. The sieving coefficient of bovine serum albumin decreased to 0.05 ± 0.03 in the 3 % CSP/BNC membrane. Moreover, the CSP/BNC membrane exhibited good hemocompatibility and cytocompatibility. The simulated dialysis results showed that the 3 % CSP/BNC membrane exhibited high clearance of urea (16.37 %/cm2) and lysozyme (3.54 %/cm2), while efficiently retaining bovine serum albumin (98.04 %/cm2). This is the first demonstration of the construction of a BNC-based hemodialysis membrane with in situ CSP formation to effectively regulate the pore properties of the membrane, making the CSP/BNC membrane a promising candidate for hemodialysis applications.

Rhodium-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3-Dipolar Nitrones.

Owing to their distinctive 1,3-dipolar structure, the catalytic asymmetric hydrogenation of nitrones to hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol and susceptibility to N-O bond cleavage. In this study, the asymmetric hydrogenation and transfer hydrogenation of nitrones were accomplished with a tethered TsDPEN-derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine), the reaction proceeds via a novel 7-membered cyclic transition state, producing chiral hydroxylamines with up to 99 % yield and >99 % ee. The practical viability of this methodology was underscored by gram-scale catalytic reactions and subsequent transformations. Furthermore, mechanistic investigations and DFT calculations were also conducted to elucidate the origin of enantioselectivity.

Design and Synthesis of Diphosphine Ligands Based on the Chiral Biindolyl Scaffold and Their Application in Transition-Metal Catalysis.

An extremely concise, scalable, and stereoselective synthesis of a privileged chiral skeleton based on 2,2'-biindolyl and commercially available chiral building blocks has been developed. This novel skeleton allows for easy access to a range of bisphosphine ligands (decagram scale, up to 58% total yield, only three steps). The synthetic method is characterized by an efficient central-to-axial chirality transfer strategy. In particular, the superior performance of the ligands has been demonstrated in diverse reactions, including several asymmetric hydrogenations, asymmetric conjugate reductions, and cycloisomerization reactions, indicating a great potential for the application of the newly developed chiral backbones in further modifications and exploration of novel chiral ligands and catalysts.

Development of a One-Step Synthesis of oxa-Spirocyclic Diphosphine Ligands Driven by Their Application in the Industrial Synthesis of Sacubitril.

Herein we have developed a highly practical and efficient one-step coupling protocol for the synthesis of chiral spiro diphosphine ligands, especially for the oxa-spiro diphosphine ligands O-SDP, which showed excellent reactivity and diastereoselectivity in the asymmetric hydrogenation of a key intermediate of Sacubitril. It should be noted that the one-step coupling protocol could be operated on a kilogram scale, and the resulting ruthenium catalyst of O-SDP could hydrogenate the key intermediate of Sacubitril on an industrial scale.

Semisynthesis, anti-oomycete and anti-fungal activities of ursolic acid ester derivatives.

Using ursolic acid (UA) as the lead compound, thirteen UA ester derivatives (3 and 7a-l) were synthesized by modifying their C-3 and C-28 positions, respectively, and their structures were well characterized by 1H NMR, 13C NMR, HRMS and melting points. Furthermore, we evaluated the anti-oomycete and anti-fungal activities of these compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that compound 7h exhibited prominent anti-oomycete and anti-fungal activities, and the median effective concentration (EC50) values of 7h against P. capsici and F. graminearum were 70.49 and 113.21 mg/L, respectively. This study suggested that the anti-oomycete and anti-fungal activities of esters synthesized by introducing acyloxy group at C-3 position of UA was more conspicuous than that of esters synthesized by introducing benzyloxy group at C-28 position. This result will pave the way for further modification of UA to develop potential new fungicides.

Assessment of reproductive toxicity in adult zebrafish (Danio rerio) following sublethal exposure to penthiopyrad.

Penthiopyrad (PO), a succinate dehydrogenase inhibitor (SDHI) fungicide, poses a potential risk to fish. Here, we investigated the adverse effects of PO on endocrine regulation and reproductive capacity in zebrafish during a 21-d sublethal exposure to PO concentrations ranging from 0.02 to 2.00 mg/L. Following exposure to PO (0.20 and 2.00 mg/L), female-specific effects including follicle necrosis, structural disturbance of the yolk follicle, fusion of cortical follicles appeared in ovarian tissue of adult females, which led to a significant reduction in fertility. Correspondingly, 0.20 and 2.00 mg/L PO led to a marked reduction in the GSI values of females, and 2.00 mg/L PO caused a 31% decline in the proportion of perinucleolar oocytes (PCO) in oocytes. In addition, testosterone (T) level was obviously suppressed and 17ß-estradiol (E2) level was increased in females after exposure to 2.00 mg/L PO. Male zebrafish treated with 0.20 and 2.00 mg/L of PO exhibited significant interstitial enlargement, edema in the testes, and reduced diameter of seminiferous tubules, along with a thinner basement membrane. The effects of PO on males were associated with significant increase in E2 level, suggesting that PO has an estrogenic effect on male fish. Greater E2 levels in serum were further supported by increased transcription levels of genes linked to the hypothalamic-pituitary-gonad-liver (HPGL) axis. Notably, transcription levels of cyp19a, er2b, era, and cyp19b was remarkably increased, exhibiting a clear link with variations in E2 levels. Overall, the present study demonstrates that PO induces reproductive impairment in zebrafish by promoting steroidogenesis.

Combinatorial Synthesis of Indole Derivatives as Anti-oomycetes Agents.

BACKGROUND: Developing high-efficiency and low-risk small-molecule green fungicide is the key to effective control of the plant pathogenic oomycetes. Indole is an important raw material for drug synthesis. Due to its unique structural skeleton, indole, and its derivatives have exhibited a wide range of biological activities. However, a study on the synthesis of novel indole derivatives as fungicidal agents against Phytophthora capsici has not yet been reported. METHODS: The important intermediates 2a-c and 3a-c were synthesized in high yields by Vilsmeier- Haack and Knoevenagel reactions with indole as the lead compound. Furthermore, different substituted benzenesulfonyl groups were introduced into the NH position of the indole ring, and twelve indole derivatives (I-a-l) were prepared. Their structures were well characterized by 1H NMR, HRMS, and melting point. RESULTS: The results showed that 2-[(N-(4-nitrobenzenesulfonyl)-indole-3)-methylene]-diethyl malonate (I-d) and 2-[(N-(4-nitrobenzenesulfonyl)-5-cyanoindole-3)-methylene]-diethyl malonate (I-l) showed more anti-oomycete activity against P. capsici than the commercialized fungicide zoxamide, with corresponding EC50 values of 26.53, 23.48 and 28.16 mg/L, respectively, and the protective effect of the compounds against P. capsici in vivo further confirmed the above results. CONCLUSION: The preliminary structure-activity relationship showed that the formyl group modification at the C-3 position of the indole ring was acceptable, and the different anti-oomycete activities of R1 and R2 were significantly different, with R1 being 5-CN > H > 6-Me, and R2 being 4-NO2 > 3-NO2, H > 4-Me.