Intramolecular Direct C–H Bond Arylation from Aryl Chlorides: A Transition-Metal-Free Approach for Facile Access of Phenanthridines

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 KO<i>t</i>-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

Palladium-Catalyzed Decarboxylative Acylation of <i>N</i>‑Nitrosoanilines with α‑Oxocarboxylic Acids

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

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

<p>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 <b>1h,</b> 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 <b>1h</b> over other PDEs was acceptable. In addition, <b>1h</b> 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.</p

Presentation_1_Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities.PDF

<p>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.</p

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. In this study, a series of novel pyrazolopyrimidinone–rivastigmine hybrids were designed, synthesized, and evaluated <i>in vitro</i>. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds <b>6c</b> and <b>6f</b> showed the best IC₅₀ values against PDE9A (<b>6c</b>, 14 nM; <b>6f</b>, 17 nM) together with the considerable inhibition against BuChE (IC₅₀, <b>6c</b>, 3.3 μM; <b>6f</b>, 0.97 μM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds <b>6c</b> and <b>6f</b> exhibited negligible toxicity, which made them suitable for the further study of AD <i>in vivo</i>

Regioselective Direct C‑3 Arylation of Imidazo[1,2‑<i>a</i>]pyridines with Aryl Tosylates and Mesylates Promoted by Palladium–Phosphine Complexes

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

The Molecular Basis for the Selectivity of Tadalafil toward Phosphodiesterase 5 and 6: A Modeling Study

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 to inhibit PDE5 and PDE6, whereas tadalafil gives a high selectivity of 1020-fold against PDE6. Till now, their molecular mechanisms of selectivity of PDE5 versus PDE6 have remained unknown in the absence of the crystal structure of PDE6. In order to elucidate its isoform-selective inhibitory mechanism, a 3D model of PDE6 was constructed by homology modeling, and its interaction patterns with tadalafil plus sildenafil were exploited by molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. The present work reveals that tadalafil exhibits a less negative predicted binding free energy of −35.21 kcal/mol with PDE6 compared with the value of −41.12 kcal/mol for PDE5, which suggests that tadalafil prefers PDE5 rather than PDE6 and confers a high selectivity for PDE5 versus PDE6. The binding free energy results for tadalafil were consistent with external bioassay studies (IC₅₀ = 5100 and 5 nM toward PDE6 and PDE5, respectively). Two important residues from the Q₂ pockets (Val782 and Leu804 in PDE5 and their corresponding Val738 and Met760 in PDE6) were further identified to account for the high selectivity of tadalafil for PDE5 versus PDE6. These findings have shed light on the continuous puzzle of why sildenafil (IC₅₀ = 74 and 6 nM toward PDE6 and PDE5, respectively) causes visual disorders because of its poor selectivity but tadalafil does not. In addition, the homology model of PDE6 can be used to design more potent and selective second-generation PDE5 inhibitors with less inhibitory potency against PDE6

Discovery and Optimization of Chromeno[2,3‑<i>c</i>]­pyrrol-9(2<i>H</i>)‑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-<i>c</i>]­pyrrol-9­(2<i>H</i>)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in <b>2</b>, 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 <b>2</b> 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 <b>2</b> is a potential candidate for the treatment of PAH

Discovery and Optimization of Chromeno[2,3‑<i>c</i>]­pyrrol-9(2<i>H</i>)‑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-<i>c</i>]­pyrrol-9­(2<i>H</i>)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in <b>2</b>, 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 <b>2</b> 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 <b>2</b> is a potential candidate for the treatment of PAH

Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent

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 <b>3r</b> that has an IC₅₀ of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that <b>3r</b> inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of <b>3r</b>, 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-<b>3r</b> reveals significantly different conformation and hydrogen bonding pattern of <b>3r</b> from those of previously published <b>28s</b>. Both <b>3r</b> and <b>28s</b> form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but <b>3r</b> shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors