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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 3a (IC50 = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 A with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.

Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor A. As a result, a potent and highly selective PDE10A inhibitor, 14·3HCl (half maximal inhibitory concentration, IC50 = 2.8 nmol/L and >3500-fold selectivity) exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50% was identified with the aid of efficient methods of binding free energy predictions. Animal PAH studies showed that the improvement offered by 14·3HCl [2.5 mg/kg, oral administration (p.o.)] was comparable to tadalafil (5.0 mg/kg, p.o.), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A−14 complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors., Graphical abstract A potent and highly selective PDE10A inhibitor, 14·3HCl (IC50 = 2.8 nmol/L and >3500-folds selectivity) with a remarkable bioavailability of 50% was obtained to verify the feasibility for the anti-PAH treatment. The crystal structure of PDE10A–14 complex illustrated the binding pattern, providing a guideline for rational design of highly selective PDE10A inhibitors.Image 1

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4a revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4a exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-β-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.

Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer’s disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC50 = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was the most potent PDE2 inhibitor, with an IC50 value of 41.5 nM. The molecular docking of PDE2-(+)-11h reveals that the 4-(trifluoromethyl)benzyl)oxyl side chain of the compound enters the H-pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD.

A challenge for sensors targeting specific enzymes of interest in their native environment for direct imaging is that they rationally exploit a highly selective fluorescent probe with a high binding affinity to provide real-time detection. Immunohistochemical staining, proteomic analysis, or recent enzymatic fluorescent probes are not optimal for tracking specific enzymes directly in living cells. Herein, we introduce the concept of designing a highly effective fluorescent probe (BVQ1814) targeting phosphodiesterase 10A with a highly potent affinity and a >1000-fold subfamily selectivity by gaining insights into the three-dimensional structural information of the active site of the catalytic pocket. BVQ1814 showed an outstanding binding affinity for PDE10A in vitro and specifically detected PDE10A in living cells, indicating that most PDE10A was probably distributed in the lysosomes. We validated the PDE10A distribution in stable mCherry-PDE10A-overexpressing HepG2 cells. This probe delineated the profile of PDE10A in tissue sections and exhibited a remarkable therapeutic effect as a PDE10A inhibitor for treating pulmonary arterial hypertension. This concept will open up a new avenue for designing a highly effective fluorescent probe for tracking receptor proteins by taking full advantage of the structural information in the ligand-binding pocket of the target of interest.

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 a novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on the PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 of 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, and remarkable pharmacodynamic effects as an anti-IPF agent. Oral administration of compound 3m (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model and prevented transforming growth factor-β-induced fibroblast-to-myofibroblast conversion in vitro, indicating that PDE1 inhibition could serve as a novel target for the efficient treatment of IPF.

Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer’s disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC50 of 2.0 nM against PDE9, showed good metabolic stability (t1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification.

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ 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. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC50 values, Graphical abstract Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for Alzheimer's disease and type 2 diabetes mellitus. A series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. Four of them exhibited excellent inhibitory activity against PDE9A and low cell toxicity. The most effective compound 11a gave the IC50 of 1.0 nmol/L towards PDE9, which was significantly better than the reference compounds PF-04447943 and BAY 73-6691.fx1

Alzheimer’s disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a superenzyme family responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently, PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have exhibited remarkable cognitive improvement effects in preclinical studies and over 15 of them have been subjected to clinical trials. The aim of this review is to summarize the outstanding progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms, and limitations of these PDE inhibitors in the treatment of AD are also rev...

A method for the transition-metal-free direct C–H arylation of unactivated arenes is developed with aryl bromides as substrates and 8-hydroxyquinoline as an efficient promoter. A variety of biaryl compounds with structural diversity are obtained in moderate to high yields. Mechanistic studies reveal that the reaction proceeds via a homolytic­ aromatic substitution pathway.

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. In this study, a series of novel pyrazolopyrimidinone–rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 μM; 6f, 0.97 μM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy m...

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 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer’s disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure–activity relationship (SAR) of lead compounds.

Accurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

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 of N-nitrosoanilines at room temperature, affording an array of 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. With the aid of only di-tert-butyl peroxide, a number of inactive cyclic ethers and cycloalkanes can be directly coupled with indole derivatives in satisfactory yields.

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 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.

An intermolecular CH arylation of unactivated arenes with aryl iodides is made viable through a transition-metal-free approach. This simple and efficient process obviates the common use of diamines or diols as the promoters. With the aid of only mixed potassium alkoxides, a number of unactivated arene CH bonds can be directly arylated through a homolytic aromatic substitution (HAS) pathway.

Direct intermolecular C-H arylation employing aryl bromide as the arene source has been developed. This process proceeds via a simple transition-metal-free pathway. With the aid of inexpensive and commercially available 2-pyridyl carbinol and potassium tert-butoxide, various unactivated arene C-H bonds can be directly arylated by aryl bromides through homolytic aromatic substitution.

The catalytic cross-dehydrogenative coupling (CDC) reaction has received intense attention in recent years. The attractive feature of this coupling process is the formation of a C-C bond from two C-H moieties under oxidative conditions. In this Focus Review, recent advances in the palladium-catalyzed CDC reactions of C(sp(2) )-H bond are summarized, with a focus on the period from 2011 to early 2013.

A transition-metal-free oxidative coupling of allylic C–H and heterocyclic/aromatic N–H bonds was performed under mild conditions. Promoted by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), up to 99% yield could be achieved.

Recently, a series of xanthone analogues has been identified as α-glucosidase inhibitors. To provide deeper insight into the three-dimensional (3D) structural requirements for the activities of these molecules, CoMFA and CoMSIA approaches were employed on 54 xanthones to construct 3D-QSAR models. Their bioactive conformations were first investigated by docking studies and optimized by subsequent molecular dynamics (MD) simulations using the homology modeled structure of the target protein. Based on the docking/MD-determined conformers, 3D-QSAR studies generated several significant models in terms of 47 molecules as the training set. The best model (CoMSIA-SHA) yielded q 2 of 0.713, r 2 of 0.967 and F of 140.250. The robustness of the model was further externally confirmed by a test set of the remaining molecules (q 2 = 0.793, r 2 = 0.902, and k = 0.905). Contour maps provided much information for future design and optimization of new compounds with high inhibitory activities towards α-glucosidase.

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer’s disease and pulmonary hypertension. However, most of the current PDE2A inhibitors have moderate selectivity over other PDEs. In the present study, we described the discovery of novel PDE2A inhibitors by structure-based virtual screening combining pharmacophore model screening, molecular docking, molecular dynamics simulations, and bioassay validation. Nine hits out of 30 molecules from the SPECS database (a hit rate of 30%) inhibited PDE2A with affinity less than 50 μM. Optimization of compound AQ-390/10779040 (IC50 = 4.6 μM) from the virtual screening, which holds a novel scaffold of benzo[cd]indol-2(1H)-one among PDE inhibitors, leads to discovery of a new compound LHB-8 with a significant improvement of inhibition (IC50 = 570 nM). The modeling studies demonstrated that LHB-8 formed an extra hydrogen bond with Asp808 and a hydrophobic interaction with Thr768, in addition to the common interactions with Gln859 and...

The ethanolic extract of the leaves of Eriobotrya japonica exhibited inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of a new triterpene (1), together with seven known triterpenoids, methyl corosolate (2), ursolic acid (3), oleanolic acid (4), methyl maslinate (5), α-amyin (6), 3β,19α,23-trihydroxy-urs-12-ene (7) and uvaol (8). The structure of compound 1 was established as 3β-hydroxyl-21β-acetoxyl-urs-12-en-28-carboxylate on the basis of interpretation of its 1D and 2D NMR and HR-ESI-MS spectroscopic data. The bioassay results verified compounds 2, 3 and 8 inhibited PDE4D2 effectively with the IC50 values of 3.06, 2.18 and 5.17 μM, respectively, which may provide a novel mechanism for the anti-inflammatory activity of the leaves of E. japonica.

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 IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.

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. With the aid of only di-tert-butyl peroxide, a number of inactive cyclic ethers and cycloalkanes can be directly coupled with indole derivatives in satisfactory yields.

N,N-Dimethyloxamic acid can be successfully employed as a carboxylate precursor in the palladium-catalyzed direct C–H carboxylation of acetanilides. The reaction proceeds smoothly under mild conditions over a broad range of substrates with high functional group tolerance, affording substituted N-acyl anthranilic acids in moderate to high yields.

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

The asymmetric vanadium-catalyzed oxidation of 1,3-dithianes from aldehydes and ketones by β-amino alcohol-derived Schiff base ligands with two stereogenic centers was investigated. Using aqueous hydrogen peroxide as the oxidant and the Schiff base 3b as a chiral ligand, a variety of 1,3-dithianes derived from aldehydes were easily converted into the corresponding mono-sulfoxides in good yields (81–88%) with excellent enantioselectivities (up to 99% ee). Additionally, 99% ee was obtained for the enantioselective vanadium-catalyzed oxidation of the 1,3-dithianes derived from ketones. We found a slight kinetic resolution when using a higher ratio of hydrogen peroxide during the oxidation of the aldehyde-derived 1,3-dithianes but not in the ketone-derived 1,3-dithianes.

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

A new polyethylene glycol (PEG) supported ligand, with the PEG chain attached to the nitrogen of TsDPEN, was synthesized using a very simple procedure. The Ru-catalyzed asymmetric transfer hydrogenation of various aromatic ketones in water was investigated with this chiral ligand. High chemical yields and enantioselectivities were obtained under very mild conditions. In addition, the chiral ligand was easily recycled several times and this catalyst was especially suitable for the preparation of chiral tetrahydronaphthalen-1-ol and 2,3-dihydro-1H-inden-1-ol (up to 98% conversion with 99% ee). The latter product can be used as the key intermediate for the synthesis of neuroprotective and anti-AChE agents Rasagiline and Ladostigil.

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 the oxidant. A variety of sulfides were smoothly converted into the corresponding sulfoxides catalyzed by the chiral vanadium–Schiff base complex. Good yields (>80 %) with excellent enantioselectivities (>99 % ee) were obtained in most cases. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Chiral ligand (S,S)-PEG-BsDPEN has been found to be efficient for the asymmetric transfer hydrogenation of various ferrocenyl ketones. With sodium formate as a hydrogen donor, PEG 2000 and water as the reacting media, the catalyst system could be recycled several times. This procedure could be scaled up to a 100 mmol or more in a common round flask which is easy to perform in ordinary laboratories. The preparation of Ugi’s amine with the ferrocenyl alcohol was also investigated.

TsDPEN derivative (3,3′,5,5′-TMTsDPEN) was synthesized and applied in asymmetric transfer hydrogenation of ketones. The influence of chiral ligands’ NCCN dihedral angles to the enantioselectivities of the reaction was discussed.

A new polyethylene glycol supported Ru catalyst was synthesized and applied in the asymmetric transfer hydrogenation of various aromatic ketones in water with high chemical yields and enantioselectivities without adding any surfactants. The catalyst could be easily recycled several times without a significant loss of enantioselectivity and activity.

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 and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

A palladium-catalyzed carboxylation of acetanilide and N,N-dimethyloxamic acid for the synthesis of N-acyl-anthranilic acids is described. N,N-Dimethyloxamic acid can act as an effective carboxylation precursor with K2S2O8 as the oxidant and Pd(OAc)2 as the catalyst.

Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite different from the previously suggested hydrolysis mechanism of cAMP for PDE4. Furthermore, the subsequent ligand exchange and the release of the product GMP have also been investigated by binding energy analysis and MD simulations. It is deduced that ligand exchange would be the rate-determining step of the whole reaction, which is consistent with many previous experimental results. The obtained mechanistic insights should be valuable for not only the rational design of more specific inhibitors toward PDE5 but also understanding the general hydrolysis mechanism of cGMP-specific PDEs.

Phosphodiesterase-4 (PDE4) is an anti-inflammatory target for treatment of asthma and chronic obstructive pulmonary disease (COPD). Here, we report the isolation and characterization of 13 compounds (G1-G13) by bioassay-guided fractionation of the ethyl acetate extraction of Gaultheria yunnanensis (FRANCH.), one of which pentacyclic triterpene (G1) has never been reported. Four of them (G1, G2, G4, and G5) inhibit PDE4 with the IC50 values

Direct C-3 arylation of imidazo[1,2-a]pyridines with aryl tosylates and mesylates has been accomplished by employing palladium(II) acetate associated with 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 of aryl sulfonates and shows excellent C-3 regioselectivity of imidazo[1,2-a]pyridine. These results represent the first examples of using tosylate- and mesylate-functionalized arenes as the electrophile partners for this regioselective direct arylation.

N-Nitroso groups in anilines (I) and (IV) function as a traceless directing group while toluene derivatives (II) serve as effective acyl precursors.

A palladium-catalyzed cascade cross-coupling of N-nitroso-anilines and toluene derivatives for the direct synthesis of N-alkyl-2-aminobenzophenones is described. N-nitroso groups in anilines can act as the traceless directing groups while toluene derivatives can serve as effective acyl precursors under mild reaction 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 with 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 of aryl sulfonates and shows excellent C-3 regioselectivity of imidazo[1,2-a]pyridine. These results represent the first examples of using tosylate- and mesylate-functionalized arenes as the electrophile partners for this regioselective direct arylation.

Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.