Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.

3D scaffolds and heterogeneous seeds are two effective ways to guide Li deposition and suppress Li dendrite growth. Herein, 3D TiO2 nanotube (TNT) arrays decorated using ultrafine silver nanocrystals (7–10 nm) through cathodic reduction deposition are first demonstrated as a confined space host for lithium metal deposition. First, TiO2 possesses intrinsic lithium affinity with large Li absorption energy, which facilitates Li capture. Then, ultrafine silver nanocrystals decoration allows the uniform and selective nucleation in nanoscale without a nucleation barrier, leading to the extraordinary formation of lithium metal importing into 3D nanotube arrays. As a result, Li metal anode deposited on such a binary architecture (TNT‐Ag‐Li) delivers a high Coulomb efficiency at around 99.4% even after 300 cycles with a capacity of 2 mA h cm−2. Remarkably, TNT‐Ag‐Li exhibits ultralow overpotential of 4 mV and long‐term cycling life over 2500 h with a capacity of 2 mAh cm–2 in Li symmetric cells. Moreover, the full battery with 3D spaced Li nanotubes anode and LiFeO4 cathode exhibits a stable and high capacity of 115 mA h g–1 at 5 C and an excellent Coulombic efficiency of ≈100% over 500 cycles.

Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.

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BACKGROUND Curcumin is a promising botanical acaricidal compound with activity against Tetranychus cinnabarinus. Calmodulin (CaM) is a key calcium ion (Ca2+) sensor that plays a vital role in calcium signaling. Overexpression of the CaM gene with inducible character occurs in curcumin‐treated mites, but its functional role remains to be further analyzed by RNA interference (RNAi) and protein expression. RESULTS A CaM gene was cloned from T. cinnabarinus (designated TcCaM). TcCaM was upregulated and the protein was activated in mites by curcumin. The susceptibility of mites to curcumin was decreased after inhibiting CaM function with anti‐CaM drug trifluoperazine (TFP) and silencing CaM transcription with RNAi, suggesting that the CaM gene is involved in the acaricidal activity of curcumin against mites. Moreover, the TFP pre‐treated Sf9 cells were resistant to curcumin‐mediated increase in [Ca2+]i levels, indicating that CaM‐mediated Ca2+ homeostasis was disturbed by curcumin. TcCaM was then re‐engineered for heterologous expression in Escherichia coli. Strikingly, our results showed that the recombinant CaM protein was directly activated by curcumin via inducing its conformational changes, its half‐maximal effective concentration (EC50) value is 0.3 μmol L‐1 in vitro, which is similar to curcumin against CaM‐expressing Sf9 cells (0.76 μmol L‐1) in vivo. CONCLUSION These results confirm that the overexpressed CaM gene is involved in the acaricidal activity of curcumin, and the mode of action of curcumin may be via activating CaM function, and thereby disrupting Ca2+ homeostasis in T. cinnabarinus. This study highlights the novel target mechanism of new acaricides, promoting our understanding of the molecular mechanism of CaM‐mediated acaricide targets in mites.

A rapid, high-resolution and effective new method for analyzing 12 diuretics by CE-ESI-MS was established in this paper. Ten diuretics (except two neutral compounds) could be fast separated by CE with a DAD at 214 nm with a 20 kV voltage within 6 min, using a 50 microm id and 48.5 cm effective length uncoated fused-silica capillary in a 40 mM ammonium formate buffer (pH 9.40). CE was coupled to the mass spectrometer applying an orthogonal electrospray interface with a triple-tube sheath liquid arrangement. The sheath liquid was composed of isopropanol-water (1:1 v/v) containing 30 mM acetic acid with a flow rate of 4 microL/min. Mass spectrum was employed in the positive mode and both full scan mode and SIM scan mode were utilized. All 12 diuretics could be detected and confirmed by MS in a single analysis. Under optimized conditions, LODs for the 12 diuretics were in the range of 0.13-2.7 micromol/L at an S/N of 3, and the correlation coefficients R(2 )were between 0.9921 and 0.9978. The RDSs (n = 5) of the method was 0.24-0.94 % for migration times and 1.6-8.8 % for peak areas. The recoveries of spiked samples of 12 diuretics were between 72.4% and 118%. The real urine samples were injected directly for analysis, with only simple filtration through a 0.22 microm membrane filter in order to remove solid particles, which may cause capillary blockage. Based on the migration times and characteristic ions, the diuretics in urine samples were detected successfully. This CE-ESI-MS method for analyzing diuretics will hopefully be applied to doping control.

Flexible and conductive hydrogels have been widely used in the field of flexible wearable sensors. However, the traditional carbon-based composite hydrogel sensors tend to present the weak adhesion and mechanical...

Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.