Bimetallic Synergy Enables Silole Insertion into THF and the Synthesis of Erbium Single-Molecule Magnets.

The potassium silole K [SiC -2,5-(SiMe ) -3,4-Ph ] reacts with [M(η -COT)(THF) ][BPh ] (M=Er, Y; COT=cyclo-octatetraenyl) in THF to give products that feature unprecedented insertion of the nucleophilic silicon centre into a carbon-oxygen bond of THF. The structure of the major product, [(μ-η  : η -COT)M(μ-L )K] (1 ), consists of polymeric chains of sandwich complexes, where the spiro-bicyclic silapyran ligand [C H OSiC (SiMe ) Ph ] (L ) coordinates to potassium via the oxygen. The minor product [(μ-η  : η -COT)M(μ-L )K(THF)] (2 ) features coordination of the silapyran to the rare-earth metal.

Dynamic Magnetic Properties of Germole-ligated Lanthanide Sandwich Complexes.

The first germole-ligated single-molecule magnets are reported, with contrasting properties found for the near-linear sandwich complexes [(η -COT)Ln(η -Cp ] , where Ln=Dy (1 ) or Er (1 ), COT is cyclo-octatetraenyl and Cp is [GeC -2,5-(SiMe ) -3,4-Me ] . Whereas 1 has an energy barrier of 120(1) cm in zero applied field and open hysteresis loops up to 10 K, the relaxation in 1 is characterized by quantum tunneling within the ground state.

Investigating the vapour phase synthesis of copper terephthalate metal organic framework thin films by atomic/molecular layer deposition.

Solventless synthesis and processing of Metal Organic Frameworks (MOFs) is critical to implement these materials in applied technologies. Vapour phase synthesis of MOF thin films is particularly suitable for such applications, but challenging compared to the conventional solution based methods. It is therefore compelling to advance and widen the vapour phase synthesis of MOF thin films.

Molecular Magnetic Materials Based on {Co (Tp*)(CN) } Cyanidometallate: Combined Magnetic, Structural and Co NMR Study.

The cyanidocobaltate of formula fac-PPh [Co ( Tp)(CN) ] ⋅ CH CN (1) has been used as a metalloligand to prepare polynuclear magnetic complexes ( Tp=hydrotris(3,5-dimethylpyrazol-1-yl)borate). The association of 1 with in situ prepared [Fe (bik) (MeCN) ](OTf) (bik=bis(1-methylimidazol-2-yl)ketone) leads to a molecular square of formula {[Co {( Tp)}(CN) ] [Fe (bik) ] }(OTf)  ⋅ 4MeCN ⋅ 2H O (2), whereas the self-assembly of 1 with preformed cluster [Co (OH )(piv) (Hpiv) ] in MeCN leads to the two-dimensional network of formula {[Co (piv) ] [Co ( Tp)(CN) ]  ⋅ 2CH CN} (3). These compounds were structurally characterized via single crystal X-ray analysis and their spectroscopic (FTIR, UV-Vis and Co NMR) properties and magnetic behaviours were also investigated.

Porphyrin and phthalocyanine-based metal organic frameworks beyond metal-carboxylates.

Given the ubiquitous role of porphyrins in natural systems, these molecules and related derivatives such as phthalocyanines are fascinating building units to achieve functional porous materials. Porphyrin-based MOFs have been developed over the past three decades, yet chemically robust frameworks, necessary for applications, have been achieved much more recently and this field is expanding. This progress is partially driven by the development of porphyrins and phthalocyanines bearing alternative coordinating groups (phosphonate, azolates, phenolates…) that allowed moving the related MOFs beyond metal-carboxylates and achieving new topologies and properties.

Vapor-Phase Infiltration inside a Microporous Porphyrinic Metal-Organic Framework for Postsynthesis Modification.

Vapor-phase infiltration (VPI), a technique derived from atomic layer deposition (ALD) and based on sequential self-limiting chemistry, is used to modify the stable microporous porphyrin-based metal-organic framework (MOF) MIL-173(Zr). VPI is an appealing approach to modifying MOFs by inserting reactants with atomic precision. The microporous nature and chemical stability of MIL-173 enable postsynthesis modification by VPI without MOF degradation even with extremely reactive precursors such as trimethylaluminum (TMA) and diethylzinc (DEZ).

Probing the Local Magnetic Structure of the [Fe (Tp)(CN) ] Building Block Via Solid-State NMR Spectroscopy, Polarized Neutron Diffraction, and First-Principle Calculations.

The local magnetic structure in the [Fe (Tp)(CN) ] building block was investigated by combining paramagnetic Nuclear Magnetic Resonance (pNMR) spectroscopy and polarized neutron diffraction (PND) with first-principle calculations. The use of the pNMR and PND experimental techniques revealed the extension of spin-density from the metal to the ligands, as well as the different spin mechanisms that take place in the cyanido ligands: Spin-polarization on the carbon atoms and spin-delocalization on the nitrogen atoms. The results of our combined density functional theory (DFT) and multireference calculations were found in good agreement with the PND results and the experimental NMR chemical shifts.

Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model.

Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15.

Thermally-Induced Spin Crossover and LIESST Effect in the Neutral [Fe(bik)(NCX)] Complexes: Variable-Temperature Structural, Magnetic, and Optical Studies (X = S, Se; bik = bis(1-methylimidazol-2-yl)ketone).

Two new iron(II) neutral complexes of bis(1-methylimidazol-2-yl)ketone (bik) with molecular formula [Fe(bik)(NCS)] () and [Fe(bik)(NCSe)] () have been synthesized and characterized by magnetic measurements, single-crystal X-ray diffraction, and solid state UV-vis spectroscopy. The temperature dependent magnetic susceptibility measurements of crystalline samples of both compound show the occurrence of a gradual spin transition centered at = 260 K and 326 K, respectively. The crystal structures of both compounds were determined at different temperatures, below and above the transition, in order to detect the structural changes associated with the spin transition.

A Redox-Active Bridging Ligand to Promote Spin Delocalization, High-Spin Complexes, and Magnetic Multi-Switchability.

A dinuclear Co complex, [Co (tphz)(tpy) ] (n=4, 3 or 2; tphz: tetrapyridophenazine; tpy: terpyridine), has been assembled using the redox-active and strongly complexing tphz bridging ligand. The magnetic properties of this complex can be tuned from spin-crossover with T ≈470 K for the pristine compound (n=4) to single-molecule magnet with an S =5/2 spin ground state when once reduced (n=3) to finally a diamagnetic species when twice reduced (n=2). The two successive and reversible reductions are concomitant with an increase of the spin delocalization within the complex, promoting remarkably large magnetic exchange couplings and high-spin species even at room temperature.

Modifications of flexible nonyl chain and nucleobase head group of (+)-erythro-9-(2's-hydroxy-3's-nonyl)adenine [(+)-EHNA] as adenosine deaminase inhibitors.

A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a-7h, 10a-c, 12, 13, 14 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-e wherein 5'C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA.

Discovery of Potent and Selective A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

Adenosine A receptor (AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-]purin-2-one derivatives that displays functional antagonism of the A receptor with a high degree of selectivity over A, A, and A receptors.

Design and synthesis of novel xanthine derivatives as potent and selective A adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases.

Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A adenosine receptor (AAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective AAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD).

Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia.

Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia.

Rational design, synthesis, and structure-activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.

Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A receptor antagonists and their biological evaluation.

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model.

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A Receptor Antagonists and Their Biological Evaluation.

Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A adenosine receptor (AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability.

Thiazole-containing conjugated polymer as a visual and fluorometric sensor for iodide and mercury.

A neutral conjugated polymer poly-p-phenylene (PPP) derivative, poly(1,4-bis-(8-(4-phenylthiazole-2-thiol)-octyloxy)-benzene) (PPT), was prepared using a simple and economical method of oxidative polymerization reaction. This newly synthesized polymer PPT was characterized by means of Fourier transform infrared spectroscopy (FT-IR), (1)H nuclear magnetic resonance ((1)H NMR), ultraviolet-visible (UV-Vis), and fluorescence spectroscopy. PPT displays fluorescence "turn-off/turn-on" characteristics and colorimetric responses to I(-) and Hg(2+).

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2.

Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability.

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed.

Discovery of a potent and selective small molecule hGPR91 antagonist.

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.

Novel biosensors for the detection of estrogen receptor ligands.

There exists a significant need for the detection of novel estrogen receptor (ER) ligands for pharmaceutical uses, especially for treating complications associated with menopause. We have developed fluorescence resonance energy transfer (FRET)-based biosensors that permit the direct in vitro detection of ER ligands. These biosensors contain an ER ligand-binding domain (LBD) flanked by the FRET donor fluorophore, cyan fluorescent protein (CFP), and the acceptor fluorophore, yellow fluorescent protein (YFP).