Clickable 4‐Oxo‐β‐lactam‐Based Selective Probing for Human Neutrophil Elastase Related Proteomes

Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper‐catalyzed alkyne–azide 1,3‐dipolar cycloaddition (CuAAC, or ′click′ chemistry) approach based on the 4‐oxo‐β‐lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure–activity relationships set the basis to develop fluorescent and biotinylated activity‐based probes as tools for molecular functional analysis. Attaching the tags to the 4‐oxo‐β‐lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC₅₀ values in the nanomolar range (56–118 nm ) displayed by the probes. The nitrobenzoxadiazole (NBD)‐based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity‐based probes with promising applications in target validation and identification, as well as diagnostic tools.     

Synthesis and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2‐{6‐[2‐(5‐Phenyl‐4H‐{1,2,4]triazol‐3‐ylsulfanyl)acetylamino]benzothiazol‐2‐ylsulfanyl}acetamide Scaffold

In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B‐NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B‐NS3 protease inhibitor with a 2‐{6‐[2‐(5‐phenyl‐4H‐[1,2,4]triazol‐3‐ylsulfanyl)acetylamino]benzothiazol‐2‐ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor ( 1 a24 , IC₅₀=3.4±0.2 μM ) of the WNV NS2B‐NS3 protease. Molecular docking of 1 a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.     

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure–activity relationship study of a small library of ω‐phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5‐bis(trifluoromethyl)phenyl group and the aromatic character of the ω‐phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so‐optimized compounds 2 [1‐(3,5‐bis(trifluoromethyl)phenyl)‐3‐(3‐(1,3‐dioxoisoindolin‐2‐yl)propyl)urea] and 21 [1‐(3,5‐bis(trifluoromethyl)phenyl)‐3‐(4‐(1,3‐dioxoisoindolin‐2‐yl)butyl)urea] exhibited dissociation constants (K_i) of 1–19 μm on the two CEases and showed either a competitive ( 2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases—monoacylglycerol lipase and fatty acid amide hydrolase—were inhibited by ω‐phthalimidoalkyl aryl ureas to a lesser extent.     

Identification of a Small‐Molecule Inhibitor of HIV‐1 Assembly that Targets the Phosphatidylinositol (4,5)‐bisphosphate Binding Site of the HIV‐1 Matrix Protein

The development of drug resistance remains a critical problem for current HIV‐1 antiviral therapies, creating a need for new inhibitors of HIV‐1 replication. We previously reported on a novel anti‐HIV‐1 compound, N²‐(phenoxyacetyl)‐N‐[4‐(1‐piperidinylcarbonyl)benzyl]glycinamide ( 14 ), that binds to the highly conserved phosphatidylinositol (4,5)‐bisphosphate (PI(4,5)P₂) binding pocket of the HIV‐1 matrix (MA) protein. In this study, we re‐evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV‐1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2‐(4‐{[3‐(4‐fluorophenyl)‐1,2,4‐oxadiazol‐5‐yl]methyl})‐1‐piperazinyl)‐N‐(4‐methylphenyl)acetamide ( 7 ), 3‐(2‐ethoxyphenyl)‐5‐[[4‐(4‐nitrophenyl)piperazin‐1‐yl]methyl]‐1,2,4‐oxadiazole ( 17 ), and N‐[4‐ethoxy‐3‐(1‐piperidinylsulfonyl)phenyl]‐2‐(imidazo[2,1‐b][1,3]thiazol‐6‐yl)acetamide ( 18 ), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV‐1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P₂ for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P₂ binding site of MA decreased the antiviral effect of compound 7 . Additionally, compound 7 displays a broadly neutralizing anti‐HIV activity, with IC₅₀ values of 7.5–15.6 μM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti‐HIV‐1 therapeutics.     

Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

Three new 3‐amino‐6‐hydroxy‐2‐piperidone (Ahp)‐containing cyclic depsipeptides, named loggerpeptins A–C ( 1 – 3 ), along with molassamide ( 4 ), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2‐amino‐butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer. Both compounds inhibited cleavage of the elastase substrate CD40 in biochemical assays; however, only 4 exhibited significant cellular activity. As CD40 and other receptor proteolytic processing culminates in NFκB activation, we assessed the effects of 4 on the expression of target genes, including ICAM‐1. ICAM‐1 is also a direct target of elastase and, in our studies, compound 4 attenuated both elastase‐induced ICAM‐1 gene expression and ICAM‐1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide also specifically inhibited the elastase‐mediated migration of highly invasive triple‐negative breast cancer cells.     

Synthesis and properties of fluorinated bis‐benzocyclobutene‐terminated arylene ether monomers

Four novel bis‐benzocyclobutene‐endcapped arylene ether monomers, 1,1′‐bis[4‐(4′‐benzocyclobutenyloxy)phenyl]‐1‐phenyl‐2,2,2‐trifluoroethane (BOPP3FE), 1,1′‐bis[4‐(4′‐benzocyclobutenyloxy)phenyl]‐1‐(3′,5′‐ditrifluoromethyl)phenyl‐2,2,2‐trifluoroethane(BOPP9FE), 2,2′‐bis[4‐(4′‐benzocyclobutenyloxy)phenyl]‐1,1,1,3,3,3‐hexfluoropropane (BOP6FP), and 2,2′‐bis[4‐(4′‐benzocyclobutenyloxy)phenyl]‐propane (BOPP) were prepared and characterized. All the four monomers showed similar curing behaviors under N₂ (Differential scanning calorimetry: extrapolated onset and peak temperatures at 225–229°C and 261–263°C) and demonstrated low and steady melt viscosities between 110 and 200°C, indicating their good processability. After cure, the resulting BCB resins exhibited high T_g (232–282°C) and excellent thermal stability (T_5% > 433°C). The resins also showed good mechanical properties with the flexural strengths of 68–88 MPa and the flexural modulus of 2.52–3.15 GPa. Moreover, the resins also exhibited low dielectric constants (2.58–2.88), low dissipation factors (2.7 to 8.4 × 10?4) and low water absorptions in boiling water for 24 h (0.29–0.59%). © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Terpenoids as Human Neutrophil Elastase (HNE) Inhibitors: A Comprehensive Review of Natural Anti-inflammatory Isoprenoids

Human neutrophil elastase (HNE) is an enzyme that plays a key role in the body‘s inflammatory response. It has been linked to several diseases such as chronic obstructive pulmonary disease (COPD), emphysema, and cystic fibrosis. As potential treatments for these diseases, HNE inhibitors are of great interest. Metabolites derived from plants, particularly terpenoids such as β-caryophyllene found in black pepper and other plants, and geraniol present in several essential oils, are recognized as significant sources of inhibitors for HNE. Because of their ability to inhibit HNE, terpenoids are considered promising candidates for developing novel therapies to treat inflammatory conditions such as COPD and emphysema. Furthermore, nature can serve as an excellent designer, and it may offer a safer drug candidate for inhibiting HNE production and activity in the future. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were searched to get relevant and up-to-date literature on terpenoids as human neutrophil elastase inhibitors. This review focuses on the isolation, chemical diversity, and inhibition of human neutrophil elastase (HNE) of various terpenoids reported from natural sources up to 2022. A total of 251 compounds from various terpenoids classes have been reported. Further, it also provides a summary of HNE inhibitors and includes a thorough discussion on the structure-activity relationship.     

Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N‐(9‐{2‐[(4‐{2‐[3‐(5‐chlorofuran‐2‐yl)‐4‐phenylisoxazol‐5‐yl]acetamido}butyl)carbamoyl]phenyl‐6‐(ethylamino)‐2,7‐dimethyl‐3H‐xanthen‐3‐ylidene}ethanaminium chloride] was found to be a selective COX‐1 inhibitor, whereas 17 (2‐[3,4‐bis(4‐methoxyphenyl)isoxazol‐5‐yl]‐1‐[6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2‐(1H)‐yl]ethanone) was found to be a sub‐micromolar selective COX‐2 inhibitor. However, both were shown to interact with P‐glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.     

Investigations on Structural and Electrochemical Properties of Some Disulfides Prepared by Schiff Base Reactions

Four different disulfides, [2,2′‐dithiobis‐(2‐mercaptoacetophenone)]‐4‐triphenylmethylthiosemicarbazone ( 1 ), [5,5′‐dithiobis‐(4‐formyl‐3‐methyl‐1‐phenylpyrazole)]‐4‐triphenylmethylthiosemicarbazone ( 2 ), bis[1‐(2‐mercaptophenyl)‐2‐(4‐(1‐phenyl‐3‐methyl)pyrazole)‐azaethene]di‐sulfide ( 3 ) and bis[1‐phenyl‐2‐(4‐(1‐phenyl‐3‐methyl‐5‐mercapto) pyrazole)‐azaethene]disulfide ( 4 ) were synthesized by Schiff base reactions. Their electrochemical behaviour was examined by cyclic voltammetry. The results show low potentials for the disulfide reduction so that these compounds are suitable for the syntheses of tridentate thiolate ligands from disulfides by electrochemical cleavage. In addition compounds 2 and 4 were characterized by X‐ray structure determination. The structures show significant differences of the S—S bonds and angles as compared to other disulfides without bulky substituents.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Merging Allosteric and Active Site Binding Motifs: De novo Generation of Target Selectivity and Potency via Natural‐Product‐Derived Fragments

The de novo design of molecules from scratch with tailored biological activity is still the major intellectual challenge in chemical biology and drug discovery. Herein we validate natural‐product‐derived fragments (NPDFs) as excellent molecular seeds for the targeted de novo discovery of lead structures for the modulation of therapeutically relevant proteins. The application of this de novo approach delivered, in synergy with the combination of allosteric and active site binding motifs, highly selective and ligand‐efficient non‐zinc‐binding ( 3 : 4‐{[5‐(2‐{[(3‐methoxyphenyl)methyl]carbamoyl}eth‐1‐yn‐1‐yl)‐2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐1‐yl]methyl}benzoic acid) as well as zinc‐binding ( 4 : 4‐({5‐[2‐({[3‐(3‐carboxypropoxy)phenyl]methyl}carbamoyl)eth‐1‐yn‐1‐yl]‐2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐1‐yl}methyl)benzoic acid) uracil‐based MMP‐13 inhibitors presenting IC₅₀ values of 11 nM ( 3 : LE=0.35) and 6 nM ( 4 : LE=0.31).     

From Type I to Type II: Design,Synthesis, and Characterization of Potent Pyrazin‐2‐ones as DFG‐Out Inhibitors of PDGFRβ

Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so‐called DFG‐in or DFG‐out conformations, respectively. Based on our former study on highly selective platelet‐derived growth factor receptor β (PDGFRβ) pyrazin‐2‐one type I inhibitors, we expanded this scaffold toward the deep pocket, yielding the highly potent and effective type II inhibitor 5 (4‐[(4‐methylpiperazin‐1‐yl)methyl]‐N‐[3‐[[6‐oxo‐5‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐3‐yl]methyl]phenyl]benzamide). In vitro characterization, including selectivity panel data from activity‐based assays (300 kinases) and affinity‐based assays (97 kinases) of these PDGFRβ type I ( 1 ; 5‐(4‐hydroxy‐3‐methoxy‐phenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐2‐one) and II ( 5 ) inhibitors showing the same pyrazin‐2‐one chemotype are compared. Implications are discussed regarding the data for selectivity and efficacy of type I and type II ligands.     

The preparation of α‐bis and α,ω‐tetrakis aromatic oxazolyl‐ and carboxyl‐functionalized polymers using 1,1‐bis[4‐(2‐(4,4‐dimethyl‐1,3‐oxazolyl))phenyl]ethylene in atom transfer radical polymerization reactions

The preparation of new compounds, 1,1‐bis[4‐(2‐(4,4‐dimethyl‐1,3‐oxazolyl))phenyl]ethanol and a new symmetrically disubstituted 1,1‐diphenylethylene derivative, 1,1‐bis[4‐(2‐(4,4‐dimethyl‐1,3‐oxazolyl))phenyl]ethylene, is described. 1,1‐Bis[4‐(2‐(4,4‐dimethyl‐1,3‐oxazolyl))phenyl]ethylene was utilized as a dioxazolyl initiator precursor for the polymerization of styrene by atom transfer radical polymerization (ATRP) methods to produce α‐bis(oxazolyl) polystyrene. The kinetic study of the polymerization process indicated that the free radical polymerization reaction for the preparation of α‐bis(oxazolyl) polystyrene follows first‐order rate kinetics with respect to monomer consumption. α,ω‐Tetrakis(oxazolyl) polystyrene was prepared by a new, in situ, controlled/living, post‐ATRP chain‐end‐functionalization reaction which involves the direct addition of 1,1‐bis[4‐(2‐(4,4‐dimethyl‐1,3‐oxazolyl))phenyl]ethylene to the ω‐terminus of the α‐bis(oxazolyl) polystyrene derivative, without the isolation and purification of the polymeric precursor. α‐Bis(carboxyl) and α,ω‐tetrakis(carboxyl) polystyrene derivatives were obtained by the quantitative chemical transformation of the oxazoline groups of the respective aromatic oxazolyl chain‐end‐functionalized polystyrene derivatives to the aromatic carboxyl groups. The organic precursor compounds, the dioxazolyl‐functionalized 1,1‐diphenylethylene derivative and the functionalized polymers were characterized using ¹H NMR and ¹³C NMR spectrometry and Fourier transform infrared spectroscopy, size‐exclusion and thin‐layer chromatography and non‐aqueous titration measurements. © 2014 Society of Chemical Industry     

Synthesis and characterization of novel soluble pyridine‐containing polyimides based on 4‐phenyl‐2,6‐bis[4‐(4‐aminophenoxy)phenyl]‐pyridine and various aromatic dianhydrides

A new kind of pyridine‐containing aromatic diamine monomer, 4‐phenyl‐2,6‐bis[4‐(4‐aminophenoxy)phenyl]‐pyridine (PAPP), was successfully synthesized by a modified chichibabin reaction of benzaldehyde and a substituted acetophenone, 4‐(4‐nitrophenoxy)‐acetophenone (NPAP), followed by a reduction of the resulting dinitro compound 4‐phenyl‐2,6‐bis[4‐(4‐nitrophenoxy)phenyl]‐pyridine (PNPP) with Pd/C and hydrazine monohydrate. The aromatic diamine was employed to synthesize a series of new pyridine‐containing polyimides by polycondensation with various aromatic dianhydrides in N‐methy‐2‐pyrrolidone (NMP) via the conventional two‐step method, i.e., ring‐opening polycondensation forming the poly (amic acid)s and further thermal or chemical imidization forming polyimides. The inherent viscosities of the resulting polyimides were in the range of 0.79–1.13 dL/g, and most of them were soluble in common organic solvents such as N,N‐dimethylacetamide (DMAc), NMP, and tetrahydrofuran (THF), etc. Meanwhile, strong and flexible polyimide films were obtained, which had good thermal stability, with the glass transition temperatures (T_g) of 268–338°C and the temperature at 5% weight loss of 521–548°C in air atmosphere, as well as outstanding mechanical properties with tensile strengths of 89.2–112.1 MPa and elongations at break of 9.5–15.4%. The polyimides also were found to possess low dielectric constants ranging from 2.53 to 3.11. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 212–219, 2007     

Light‐emitting polymers containing 2,3,4,5‐tetraphenylthiophenyl moiety and different pendent groups

By appropriate chemical reaction, different substituents can be selectively attached to the four phenyl rings present in 2,3,4,5‐tetraphenylthiophene (TP) to prepare monomers, namely 2,5‐bis(4‐bromophenyl)‐3,4‐diphenylthiophene (BTP), 2,5‐bis(4‐bromophenyl)‐3,4‐bis[4‐(nonan‐1‐one)phenyl] thiophene (BTP‐N2) and 2,5‐bis(4‐bromophenyl)‐3,4‐bis[4‐(2‐heptyl‐4‐phenylquinoline)phenyl]thiophene (BTP‐Qu2). Three light‐emitting polymers, PTP, PTP‐N2 and PTP‐Qu2, with the common TP backbone were prepared by zero‐valent nickel‐catalyzed polymerization of BTP, BTP‐N2 and BTP‐Qu2 monomers, respectively. The substituent on the 3,4‐phenyl rings of the TP framework has a profound effect on the polymer properties. Without any 3,4‐substituent, the rigid PTP polymer has low solubility in organic solvents. With the flexible nonanoyl substituent, the corresponding polymer, PTP‐N2, has improved solubility but low quantum efficiency (Φ_F) due to the carbonyl group which enhances intersystem crossing. With both flexible chain and bulky 4‐phenylquinoline (PQ) ring substituents, PTP‐Qu2 has good solubility and an enhanced Φ_F since the introduction of both flexible chain and bulky PQ ring substituents prevents close chain packing. All three polymers exhibit similar emission spectra despite the distinct difference in the absorption pattern of PTP‐Qu2 compared with those of PTP and PTP‐N2. In the case of PTP‐Qu2, there is energy transfer from the PQ pendent ring to the TP backbone and results in emission similar to PTP and PTP‐N2. The TP backbone common in all the three polymers is responsible for the emission from the corresponding excited states. The electrochemical properties of PTP‐Qu2 were also investigated. Copyright © 2005 Society of Chemical Industry     

N‐Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

Persistent opening of the mitochondrial permeability transition pore (PTP), an inner membrane channel, leads to mitochondrial dysfunction and renders the PTP a therapeutic target for a host of life‐threatening diseases. Herein, we report our effort toward identifying small‐molecule inhibitors of this target through structure–activity relationship optimization studies, which led to the identification of several potent analogues around the N‐phenylbenzamide compound series identified by high‐throughput screening. In particular, compound 4 (3‐(benzyloxy)‐5‐chloro‐N‐(4‐(piperidin‐1‐ylmethyl)phenyl)benzamide) displayed noteworthy inhibitory activity in the mitochondrial swelling assay (EC₅₀=280 nm ), poor‐to‐very‐good physicochemical as well as in vitro pharmacokinetic properties, and conferred very high calcium retention capacity to mitochondria. From the data, we believe compound 4 in this series represents a promising lead for the development of PTP inhibitors of pharmacological relevance.     

Fluorinated polybenzimidazopyrrolones with excellent alkaline‐hydrolysis resistance

Two novel aromatic tetraamines containing bulky lateral phenyl unit and multiple trifluoromethyl groups, 1,1‐bis[4‐(3′,4′‐diaminophenoxy)phenyl]‐1‐(3″‐trifluoromethylphenyl)?2,2,2‐trifluoroethane (6FTA) and 1,1‐bis[4‐(3′,4′‐diaminophenoxy)phenyl]‐1‐[3″,5″‐bis(trifluoromethyl)phenyl]‐2,2,2‐trifluoroethane (9FTA) were synthesized and characterized. A series of fluorinated aromatic polybenzimidazopyrrolones (polypyrrolones, PPys) were synthesized via a two‐step polycondensation procedure. The inherent viscosities of the precursors, poly(amide amino acid) (PAAA), ranged from 0.39 dL/g to 0.54 dL/g. All the FPPys were amorphous. The freestanding FPPy films could be prepared, which exhibited good thermal stability with the glass transition temperature of 315–389°C, the temperatures of 5% weight loss (T_5%) of 497–535°C in nitrogen and residual weight retention at 700°C over 60%. All the FPPy films exhibited excellent alkaline‐hydrolysis resistance which retained their original shapes and toughness after boiling 7 days in 10% sodium hydroxide solution. Also after boiling 8 h in 10% sodium hydroxide solution, the tensile strength could retain as high as 56% of the original values. The alkaline‐hydrolysis resistance was much better than the polyimides which had similar chemical structures. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014 , 131, 40041.     

A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitors

Microsomal prostaglandin E₂ synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein–ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-[(2-{[(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide ( 6 ) and N-(4-methoxy-3-{[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide ( 8 ), as non-acidic mPGES-1 inhibitors with IC₅₀ values of 1.2 and 1.3 μm , respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC₅₀: 0.3–0.6 μm ). The unprecedented chemical structures of 6 and 8 , which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties.     

Synthesis and in vivo Evaluation of Fluorine‐18 and Iodine‐123 Pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors

Imaging agents that target adenosine type 2A (A_2A) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson′s disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A_2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A_2A‐specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [¹²³I]MNI‐420 and [¹⁸F]MNI‐444. Herein we describe the development of both of these radiotracers by selection from a series of A_2A ligands, based on the pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A_2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine‐18 or iodine‐123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7‐(2‐(4‐(4‐(2‐[¹⁸F]fluoroethoxy)phenyl)piperazin‐1‐yl)ethyl)‐2‐(furan‐2‐yl)‐7H‐pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]pyrimidin‐5‐amine ([¹⁸F]MNI‐444) and 7‐(2‐(4‐(2‐fluoro‐4‐[¹²³I]iodophenyl)piperazin‐1‐yl)ethyl)‐2‐(furan‐2‐yl)‐7H‐imidazo[1,2‐c]pyrazolo[4,3‐e]pyrimidin‐5‐amine ([¹²³I]MNI‐420) as PET and SPECT radiopharmaceuticals for mapping A_2A receptors in brain.     

Synthesis and characterization of organosoluble poly(arylate‐imide)s prepared from direct polycondensation of bis(trimellitimide)‐diacids and various bisphenols

Three diimide‐diacids, 2,2‐bis[4‐(4‐trimellitimidophenoxy)phenyl]hexafluoropropane ( I‐A ), 2,2‐bis[4‐(4‐trimellitimidophenoxy)phenyl]propane ( I‐B ), and 5,5′‐bis[4‐ (4‐trimellitimidophenoxy)phenyl]hexahydro‐4,7‐methanoindan ( I‐C ), were prepared by the azeotropic condensation of trimellitic anhydride with three analogous diamines. Three series of alternating aromatic poly(arylate‐imide)s, having inherent viscosities of 0.41–0.82 dL/g, were synthesized from these diimide‐diacids ( I‐A , I‐B , and I‐C ) with various bisphenols by direct polycondensation using diphenyl chlorophosphate and pyridine as condensing agents. All of the polymers were readily soluble in a variety of organic solvents such as N‐methyl‐2‐pyrrolidone, N,N‐dimethylacetamide, and even in the less polar tetrahydrofuran. These polymers could be cast into transparent and tough films, which had strength at break values ranging from 73 to 98 MPa, elongation at break from 6 to 11%, and initial modulus from 1.6 to 2.2 GPa. The softening temperatures of the polymers were recorded at 145–248°C. They had 10% weight loss at a temperature above 450°C and left 35–51% residue even at 800°C in nitrogen. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 3818–3825, 2003