A palladium-catalyzed oxidative C–H bond functionalization/ortho-acylation of acetanilides using easily accessible aldehyde as the acyl source is described. In presence a Pd(TFA)2 catalyst and tert-butylhydroperoxide at 90 °C in general, an array ortho-acylacetanilides can be afforded good yields.

A palladium-catalyzed cascade cross-coupling of acetanilide and toluene for the synthesis ortho-acylacetanilide is described. Toluene derivatives can act as effective acyl precursors (upon sp(3)-C-H bond oxidation by a Pd/TBHP system) in oxidative coupling between two C-H bonds. This dehydrogenative Pd-catalyzed ortho-acylation proceeds under mild reaction conditions.

A C–H arylation with aryl chloride is made viable through a transition-metal-free approach. In the presence of simple diol associating KOt-Bu, various phenanthridine derivatives can be conveniently accessed. particular, only 10 mol % and inexpensive ethylene glycol required for this protocol. These results represent first general examples chloride/C–H coupling under conditions.

Direct C-3 arylation of imidazo[1,2-a]pyridines with aryl tosylates and mesylates has been accomplished by employing palladium(II) acetate associated SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) or L1 (2-(2-(diisopropylphosphino)phenyl)-1-methyl-1H-indole). This catalyst system can be applied to a wide range sulfonates shows excellent regioselectivity imidazo[1,2-a]pyridine. These results represent the first examples using tosylate- mesylate-functionalized arenes as electrophile...

Accurate prediction of absolute protein–ligand binding free energy could considerably enhance the success rate structure-based drug design but is extremely challenging and time-consuming. Free perturbation (FEP) has been proven reliable limited to relative energies similar ligands (with only minor structural differences) in with a same target practical applications. Herein, Gaussian algorithm-enhanced FEP (GA-FEP) protocol developed simulation performance, enabling efficiently carry out...

A palladium-catalyzed cascade cross-coupling of N-nitroso-anilines and toluene derivatives for the direct synthesis N-alkyl-2-aminobenzophenones is described. N-nitroso groups in anilines can act as traceless directing while serve effective acyl precursors under mild reaction conditions.

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 0.6 nM >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows inhibits the mRNA expression phosphoenolpyruvate carboxykinase glucose 6-phosphatase. These activities 3r, together with reasonable pharmacokinetic properties no acute toxicity at 1200 mg/kg dosage, suggest its hypoglycemic...

A palladium-catalyzed oxidative C–H bond decarboxylative acylation of N-nitrosoanilines using α-oxocarboxylic acid as the acyl source is described. The catalyst Pd(OAc)2 and oxidant (NH4)2S2O8 enabled ortho-acylation at room temperature, affording an array N-nitroso-2-aminobenzophenones in moderate to excellent yields.

Cross-dehydrogenative-coupling (CDC) between C–H/C–H bonds of indoles and cyclic ethers/cycloalkanes is made viable through a simple transition-metal-free pathway.

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported be a promising target for PAH based on the studies with nonselective PDE inhibitor papaverine, but little progress has been made confirm practical application of PDE10 inhibitors. To validate whether is ameliorated by inhibition rather than other isoforms, here we report an integrated...

A general C–H arylation of unactivated arenes by aryl/heteroaryl bromides in the presence 2-pyridyl carbinol and potassium <italic>tert</italic>-butoxide is described.

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most the current PDE2A inhibitors have moderate selectivity over other PDEs. In present study, we described discovery novel by structure-based virtual screening combining pharmacophore model screening, molecular docking, dynamics simulations, bioassay validation. Nine hits out 30 molecules from SPECS database (a hit rate 30%) inhibited with affinity less...

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 chromeno[2,3-c]pyrrol-9(2H)-one derivatives selective orally bioavailable against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits desirable inhibitory potency 5.6 nM with remarkable selectivity well excellent pharmacokinetic properties an oral bioavailability...

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease lacking effective therapy. To identify whether phosphodiesterase-1 (PDE1) inhibition could act as novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, remarkable pharmacodynamic effects...

Abstract Novel Schiff base ligands derived from β‐amino alcohols with two stereogenic centers were prepared and used in the preparation of optically pure sulfoxides by using aqueous hydrogen peroxide as oxidant. A variety sulfides smoothly converted into corresponding catalyzed chiral vanadium–Schiff complex. Good yields (&gt;80 %) excellent enantioselectivities (&gt;99 % ee ) obtained most cases. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2009)

Great attention has been paid to the clinical significance of phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and vardenafil widely used for erectile dysfunction. However, sildenafil causes side effects on visual functions since it shows similar potencies inhibit PDE5 PDE6, whereas tadalafil gives a high selectivity 1020-fold against PDE6. Till now, their molecular mechanisms versus PDE6 have remained unknown in absence crystal structure In order elucidate its...

Abstract Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized evaluated a novel series PDE9 with ability to chelate metal ions. The bioassay results showed that most these molecules strongly inhibited activity. Compound 16 an IC 50 34 nM against more than 55-fold selectivity other PDEs. In addition, this compound displayed remarkable...

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

Vascular dementia (VaD) is the second commonest type of which lacks efficient treatments currently. Neuroinflammation as a prominent pathological feature VaD, highly involved in development VaD. In order to verify therapeutic potential PDE1 inhibitors against anti-neuroinflammation, memory and cognitive improvement were evaluated vitro vivo by potent selective inhibitor 4a. Also, mechanism 4a ameliorating neuroinflammation VaD was systematically explored. Furthermore, optimize drug-like...

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, calcium antagonist commonly used to improve hypertension, was reported have inhibition PDE1. Herein, series of nimodipine analogues were discovered novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity PDE1C (IC50 = 10 nM), high selectivity over other PDEs except for...