Structure-based discovery of orally efficient inhibitors unique interactions with H-pocket of PDE8 for the treatment of vascular dementia.

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe . However, compound is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors.

Comparative analysis of bacterioplankton assemblages from two subtropical karst reservoirs of southwestern China with contrasting trophic status.

Although bacterioplankton play an important role in aquatic ecosystems, less is known about bacterioplankton assemblages from subtropical karst reservoirs of southwestern China with contrasting trophic status. Here, 16S rRNA gene next-generation sequencing coupled with water chemistry analysis was applied to compare the bacterioplankton communities from a light eutrophic reservoir, DL Reservoir, and a mesotrophic reservoir, WL Reservoir, in subtropical karst area of southwestern China. Our findings indicated that Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Cyanobacteria and Verrucomicrobia dominated bacterioplankton community with contrasting relative frequency in the two subtropical karst reservoirs.

Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors.

To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound (IC = 0.010 μM) with high selectivity with a reasonable druglike profile.

Near-Infrared Phosphorescence Emission of Binuclear Mn(II) Based Metal-Organic Framework for Efficient Photoelectric Conversion.

The development of metal-organic framework (MOF) based room-temperature phosphorescence (RTP) materials has raised extensive concern owing to their widespread applications in the field of anti-counterfeiting, photovoltaics, photocatalytic reactions, and bio-imaging. Herein, one new binuclear Mn(II) based 3D MOF [Mn(L)(BMIB)·(HO)] () (HL = 3,5-bis(3,5-dicarboxylphenxoy) benzoic acid, BMIB = tran-4-bis(2-methylimidazolyl)butylene) has been synthesized by a facile hydrothermal process. In , the protonated BMIB cations show infinite π-stacking arrangement, residing in the channels of the 3D network extended by L ligand and binuclear Mn(II) units.

Ionic liquid induced highly dense assembly of porphyrin in MOF nanosheets for photodynamic therapy.

Two-dimensional (2D) metal-organic framework (MOF) nanosheets have emerged as a new member of 2D nanomaterials for molecular sieving, energy conversion and storage, catalysis and biomedicine. In this paper, a highly dense assembly of porphyrin achievable in porphyrin-integrated MOF nanosheets induced by an ionic liquid is obtained by sonication exfoliation of its bulk crystals. The 2D layered structure MOF, [BMI]2[Ca3(H2TCPP)2(μ2-OH2)2(H2O)2] (1), was firstly prepared by using the ionic liquid assisted synthetic method (H6TCPP = meso-tetra(carboxyphenyl) porphyrin, BMI = 1-butyl-3-methylimidazolium).

The immunomodulatory role of PDEs inhibitors in immune cells: therapeutic implication in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells.

Aqueous-phase detection of antibiotics and nitroaromatic explosives by an alkali-resistant Zn-MOF directed by an ionic liquid.

An alkali-resistant Zn-MOF directed by [BMI]Br ionic liquid, (BMI)[Zn(ptptc)] (1), based on a π-electron-rich terphenyl-tetracarboxylic acid, has been synthesized under the combination of hydro/solvothermal and ionothermal condition (BMI = 1-butyl-3-methylimidazolium, Hptptc = -terphenyl-3,3'',5,5''-tetracarboxylic acid). In 1, the trinuclear Zn(ii) clusters are linked by the organic moieties of the ptptc ligands, resulting in a 3D anionic framework structure with highly disordered [BMI] cations filled in the pores. 1 exhibits good chemical stability in water and NaOH solutions (pH range of 7-12), which allow it to detect antibiotics and nitroaromatic explosives in an aquatic system.

Spatial and temporal dynamics of bacterioplankton community composition in a subtropical dammed karst river of southwestern China.

River damming influences the hydro-physicochemical variations in karst water; however, such disruption in bacterioplankton communities has seldom been studied. Here, three sampling sites (city-river section, reservoir area, and outflow area) of the Ca -Mg -HCO -SO water type in the dammed Liu River were selected to investigate the bacterioplankton community composition as identified by high-throughput 16S rRNA gene sequencing. In the dammed Liu River, thermal regimes have been altered, which has resulted in considerable spatial-temporal differences in total dissolved solids (TDSs), oxidation-reduction potential (Eh), dissolved oxygen (DO), and pH and in a different microenvironment for bacterioplankton.

Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer's Disease.

A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer's Disease (AD) agents. Among these target compounds, 11a (AChE: IC = 0.048 μM; PDE9A: IC = 0.

Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension.

To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC of 0.32 nM with remarkable selectivity and druglike profile.

Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors.

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPAR agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered.

Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC below 200 nM, and showed good antioxidant capacities in the ORAC assay.

Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer's Disease.

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet.

Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension.

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.

[Effects of Bisphenol A on Characteristics of Paddy Soil Microbial Community Under Different Cultural Conditions].

Bisphenol A (BPA) is widely known as a typical synthetic environmental hormone. Effects of BPA concentrations and aerations on soil microbial communities were rarely reported. This paper presented the studies on effects of various concentrations of BPA (0, 0.