Novel 1,3,4-oxadiazole hybrids of 3-n-butylphthalide derivatives as potential anti-ischemic stroke agents.

In continuation of our program to search for novel potential anti-ischemic stroke agents, a series of 1,3,4-oxadiazole and sulfoxide hybrids of phthalide derivatives was designed and synthesized in this study to evaluate their anti-ischemic stroke activity. Among them, compounds 5b, 5d, 5 l, and 5 m exhibited excellent inhibitory effects on platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA). In particular, compound 5b possessed considerable antithrombotic activity in animal models, as demonstrated by the effective alleviation of carrageenan-induced and FeCl3-induced thrombosis in tail and carotid arteries, respectively. Notably, intraperitoneal administration of compound 5b could better protect the brain from injury caused by ischemia/reperfusion in rats compared with precursor 3-n-butylphthalide. Further pharmacokinetics, liver microsomal stability, and PAMPA-BBB assays also indicated that compound 5b had relatively high bioavailability, metabolic stability, and BBB permeability. Moreover, compound 5b showed a safety profile that was superior to the clinical drugs clopidogrel, aspirin, and 3-n-butylphthalide in the mouse-tail bleeding assay. Finally, molecular docking predicted that the potential target of the antiplatelet aggregation activity of compound 5b was P2Y12 receptor. This research provides a novel candidate compound for the treatment of ischemic stroke.

Design and synthesis of novel 2,2-dimethylchromene derivatives as potential antifungal agents.

In order to find novel environment-friendly and effective antifungal agents, four series of 2,2-dimethyl-2H-chromene derivatives were designed, synthesized and characterized by spectroscopic analysis. The antifungal activities of all the target compounds against nine phytopathogenic fungi were evaluated in vitro. Preliminary results indicated that most of the target compounds exhibited obvious antifungal activity at the concentration of 50 µg/mL. Among them, compound 4j displayed more promising antifungal potency against Fusarium solani, Pyricularia oryzae, Alternaria brassicae, Valsa mali and Alternaria alternata strains than the two commercially available fungicides chlorothalonil and hymexazol, with the corresponding EC50 values of 6.3, 7.7, 7.1, 7.5, 4.0 µg/mL, respectively. Moreover, the cell experiments results suggested that the target compounds had low cytotoxicity to the PC12 cell. This research will provide theoretical basis for the future application of 2,2-dimethyl-2H-chromenes as botanical fungicides in agriculture. Four series of novel, potent and low-toxicity 2,2-dimethyl-2H-chromene derivatives were designed and synthesized as agricultural antifungal agents. The in vitro antifungal experiments showed that compound 4j exhibited higher antifungal efficacy against five strains than the two commercially-available fungicides chlorothalonil and hymexazol.

Synthesis and evaluation of imidazo[1,2-a]quinoxaline derivatives as potential antifungal agents against phytopathogenic fungi.

To discover novel and effective potential agricultural antifungal agents, various kinds of imidazo[1,2-a]quinoxaline derivatives were designed, and synthesized from available and inexpensive reagents. Their antifungal activities were first evaluated against ten typical phytopathogenic fungi. The in vitro antifungal activity showed that some compounds exhibited more obvious broad-spectrum fungicidal activity than the two commercially-available fungicides chlorothalonil and hymexazol. Valsa mali and Botrytis cinerea strains exhibited the highest susceptibility with EC50 values of 1.4-27.0 µg/mL to more than ten compounds. Compounds 5c and 5f showed the most promising inhibitory effects against Valsa mali (EC50 = 5.6 µg/mL) and Fusarium solani (EC50 = 5.1 µg/mL), respectively. Preliminary studies on the mechanism of action indicated that the imidazo[1,2-a]quinoxaline skeleton likely exerted its antifungal effects by disrupting hyphal differentiation, spore germination, and germ tube growth. Moreover, the cell experiment results indicated that these target compounds possessed good safety to BV2 cells. Overall, compounds 5c and 5f can be considered candidate compounds against specific fungi for further detailed research. This study can provide a theoretical basis for the application of imidazo[1,2-a]quinoxaline scaffolds as novel fungicides in agriculture.

Natural Products-Based Fungicides: Synthesis and Antifungal Activity against Plant Pathogens of 2H-Chromene Derivatives.

Aiming to search for novel potential antifungal agents, forty 2H-chromene analogs were designed, synthesized and their antifungal activity against some typical plant pathogenic fungi were firstly evaluated. The in vitro antifungal bioassays showed that some of the target compounds exhibited comparable or better inhibition activities than the commercial agricultural fungicide hymexazol. Especially compound 1m displayed more promising fungicidal effect against Alternaria alternate (EC50 =9.9 µg/mL) and Botrytis cinerea (EC50 =9.4 µg/mL), which was significantly superior to hymexazol. Moreover, in vivo protective effects results also indicated that compound 1m had an excellent potential for further development as a new botanical pesticide.

Synthesis and antifungal activity of imidazo[1,2-b]pyridazine derivatives against phytopathogenic fungi.

A series of 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives have been synthesized and characterized with spectroscopic analyses. The antifungal activities of these compounds against nine phytopathogenic fungi were evaluated by the mycelium growth rate method. The in vitro antifungal bioassays indicated that most of compounds displayed excellent and broad-spectrum antifungal activities. Especially, compounds 4a, 4c, 4d, 4l and 4r exhibited 1.9-25.5 fold more potent than the commercially available fungicide hymexazol against Corn Curvalaria Leaf Spot (CL), Alternaria alternate (AA), Pyricularia oryzae (PO) and Alternaria brassicae (AB) strains. Structure-activity relationship analysis showed that the enhanced antifungal activity is significantly affected by the substituents on the benzene ring and pyridazine ring.

Design, Synthesis and Antifungal Activities of 6-Substituted 3-Butylphthalide Derivatives against Phytopathogenic Fungi.

In order to discover novel potential antifungal agents, a series of 6-substituted 3-butylphthalide derivatives were designed, synthesized and evaluated for their antifungal activities against nine phytopathogenic fungi. Preliminary bioassay tests showed that five 3-butylphthalide derivatives exhibited more potent antifungal activities than hymexazol at the concentration of 50 µg/mL. Especially, 3-butyl-6-nitro-2-benzofuran-1(3H)-one and 3-butyl-6-hydroxy-5-nitro-2-benzofuran-1(3H)-one had significant fungicidal activity against some phytopathogenic fungi. The EC50 of 3-butyl-6-nitro-2-benzofuran-1(3H)-one against FS, FO and FG were 6.6, 9.6 and 16.0 µg/mL, respectively. The EC50 of 3-butyl-6-hydroxy-5-nitro-2-benzofuran-1(3H)-one against BC, PO, VM, SS and AS were 6.3, 5.9, 10.0, 4.5 and 8.4 µg/mL, respectively. The preliminary structure-activity relationships (SARs) of all target compounds were also investigated.

Serum Vaspin Levels in Gestational Diabetes Mellitus: A Meta-Analysis.

The objective of this study was to evaluate the potential relationship between serum vaspin levels and gestational diabetes mellitus (GDM). The PubMed, EBSCO, Web of Science, the Cochrane Library, and the China National Knowledge Infrastructure (CNKI) database were searched for articles published before December 2022. The publication language was restricted to English and Chinese. A meta-analysis was conducted by combining all studies that met the inclusion and exclusion criteria. Twenty-two studies (1990 women with GDM and 1597 pregnant women without GDM) were ultimately included in this meta-analysis. The meta-analysis showed that the serum vaspin levels are significantly higher in GDM compared with the controls (standardized mean difference: 0.720, 95% confidence interval: 0.440-1.000, Z = 5.041, P < 0.001). Subgroup analyses by stage of pregnancy and body mass index showed results similar to the overall outcome. No publication bias was identified, and the sensitivity analysis confirmed the robustness of the final result. Our results show that the serum vaspin levels are significantly higher in GDM. These findings suggest that high vaspin concentration is closely related to GDM and the serum vaspin levels might be a potential biomarker to indicate risk of GDM, more randomized control trials comparing the expression levels of vaspin between early and standard diagnosis of GDM are needed to strengthen our findings.

Design and synthesis of novel benzoxazole/chromene-phthalide scaffolds hybrids as potential natural products-based fungicide.

Phthalide, benzoxazole, and chromene are important heterocyclic skeletons with extensive biological activities. In order to develop novel potential antifungal agents, twenty-two benzoxazole/chromene-containing phthalide derivatives were prepared, and their fungicidal activity against nine common plants pathogenic fungi were evaluated in vitro. The EC50 values indicated that compound Z-4b displayed superior antifungal activity against P. oryzae (11.0 µg/mL), F. solani (8.5 µg/mL), P. capsici (27.8 µg/mL), V. mali (3.1 µg/mL) and A. brassicae (4.3 µg/mL) strains, which was more potent than the two commercialized fungicides hymexazol and chlorothalonil. In addition, the structure-activity relationship analysis demonstrated that the combination site of oxazolamide with phthalide has an important effect on antifungal activity. This research offers a potential compound for the development of novel agricultural fungicides.

Design and synthesis of novel n-butyphthalide derivatives as promising botanical fungicides.

In order to obtain novel botanical fungicides, three series of novel 6-substituted n-butyphthalide derivatives have been designed and synthesized via nucleophilic addition, reduction, nitrification, amination, sulfonation, Sandmeyer and Suzuki reaction. The mycelium growth rate method was used to evaluate the inhibition activity against eight phytopathogenic fungi in vitro. Preliminary bioassay tests showed that compounds 6f, 6n, 6p, 6r and 7a exhibited better activity for some fungi at 50 µg/mL than the positive drug hymexazol and lead compound n-butyphthalide (NBP). The preliminary structure-activity relationships indicated that the antifungal activity is significantly affected by the substituents on the benzene ring.

Neolignan Constituents with Potential Beneficial Effects in Prevention of Type 2 Diabetes from Viburnum fordiae Hance Fruits.

Nine new neolignan glycosides (1-9), viburfordosides A-I, two new neolignans, fordianes A and B (10, 11), and seven known analogues (12-18) have been isolated and identified from the fruits of Viburnum fordiae Hance. The structures and absolute configurations of undescribed neolignan constituents were identified by chemical methods and spectroscopic analyses. The α-glucosidase inhibitory, ABTS•+ and DPPH• scavenging, and anti-inflammatory activities of these secondary metabolites were evaluated. Some of them exhibited significant potency in inhibiting α-glucosidase and scavenging free radicals. Among the 14 metabolites that were found to have the capacity to inhibit NO production in LPS-stimulated RAW264.7 macrophage cells, compounds 2, 4, 6, 10, 11, 14, 17, and 18 were potent with IC50 values of 10.88-41.10 µM. These results support that V. fordiae fruits possessing the neolignan compounds may serve as both a functional food and a medicinal resource to prevent and treat type 2 diabetes (T2D).

Chemical constituents from Viburnum fordiae Hance and their anti-inflammatory and antioxidant activities.

Three new neolignans, fordianoles A-C (1-3), characterized as (7S,8R)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneolignan-7,7',9-triol, (7R,8R)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneolignan-7,7',9-triol, and (7R,8R)-4-hydroxy-3,3',5'-trimethoxy-8,4'-oxyneolignan-7,9,9'-triol-7'-one, together with an unusual γ-lactone, 3-(3,4-dihydroxyphenyl)-4-pentanolide (4), and twenty-five known compounds (5-29) were isolated from the aerial parts of Viburnum fordiae Hance. Their structures including absolute configurations were determined by spectroscopic and chemical methods. Among them, compounds 6, 7, 11-15, 17-28 were isolated from the Viburnum genus for the first time. The anti-inflammatory and antioxidant activities of all compounds were evaluated in vitro. Compounds 15, 19, 20 and 29 showed significant inhibitory activity on NO production in RAW264.7 cells stimulated by LPS with IC50 values ranging from 8.60 to 13.92 µM. Meanwhile, compounds 1-4, 15, 19, 20, 22, 23, 25, 26 and 29 exhibited varying antioxidant activities through DPPH, ABTS free radical scavenging and FRAP assays.