First cocrystal of esculetin: Simultaneously optimized in vitro/vivo properties and antioxidant effect.

Esculetin (ELT) is one of the best-known and simplest coumarins with powerful natural antioxidant effects but insoluble and difficult to absorb. In order to overcome the problems, cocrystal engineering was first applied to ELT in this paper. Nicotinamide (NAM) was selected as the coformer for its excellent water solubility and potential synergistic antioxidant effect with ELT. The structure of the ELT-NAM cocrystal was successfully prepared and characterized by IR, SCXRD, PXRD, and DSC-TG. Furthermore, the in vitro/vivo properties and antioxidant effects of the cocrystal were adequately studied. The results highlight that the ELT obtained tremendous improvements in water solubility and bioavailability after cocrystal formation. Meanwhile, the synergistic enhancement of ELT with NAM in antioxidant effect was demonstrated by the DPPH assay. Ultimately, the simultaneously optimized in vitro/vivo properties and antioxidant activity of the cocrystal created an improved practical effect of hepatoprotective in rat experiments. The investigation is significant for developing coumarin drugs represented by ELT.

Phosphorylation of Raptor by p38beta participates in arsenite-induced mammalian target of rapamycin complex 1 (mTORC1) activation.

Cell growth is influenced by environmental stress. Mammalian target of rapamycin (mTOR), the central regulator of cell growth, can be positively or negatively regulated by various stresses through different mechanisms. The p38 MAP kinase pathway is essential in cellular stress responses. Activation of MK2, a downstream kinase of p38α, enhances mTOR complex 1 (mTORC1) activity by preventing TSC2 from inhibiting mTOR activation. The p38ß-PRAK cascade targets Rheb to inhibit mTORC1 activity upon glucose depletion. Here we show the activation of p38ß participates in activation of mTOR complex 1 (mTORC1) induced by arsenite but not insulin, nutrients, anisomycin, or H(2)O(2). Arsenite treatment of cells activates p38ß and induces interaction between p38ß and Raptor, a regulatory component of mTORC1, resulting in phosphorylation of Raptor on Ser(863) and Ser(771). The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation. Our results shown here and in previous work demonstrate that the p38 pathway can regulate different components of the mTORC1 pathway, and that p38ß can target different substrates to either positively or negatively regulate mTORC1 activation when a cell encounters different environmental stresses.

Coumarin and 3,4-dihydroquinolinone derivatives: Synthesis, antidepressant activity, and molecular docking studies.

BACKGROUND: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. METHODS: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. RESULTS: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. CONCLUSION: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

Design and Synthesis of Novel 4-Hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one Derivatives for Use as Herbicides and Evaluation of Their Mode of Action.

In order to develop a novel herbicide containing the ß-triketone motif, a series of 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one derivatives were designed and synthesized. The bioassay results showed that compound II15 had good pre-emergent herbicidal activity even at a dosage of 187.5 g ha-1. Moreover, compound II15 showed a broader spectrum of weed control when compared with a commercial herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), and displayed good crop safety to Triticum aestivum L. and Zea mays Linn. when applied at 375 g ha-1 under pre-emergence conditions, which indicated its great potential as a herbicide. More importantly, studying the molecular mode of action of compound II15 revealed that the novel triketone structure is a proherbicide of its corresponding phenoxyacetic acid auxin herbicide, which has a herbicidal mechanism similar to that of 2,4-D. The present work indicates that the 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one motif may be a potential lead structure for further development of novel auxin-type herbicides.