Organic Salts of p-Coumaric Acid and Trans-Ferulic Acid with Aminopicolines.

p-Coumaric acid (pCA) and trans-ferulic acid (TFA) were co-crystallised with 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP) producing organic salts of (pCA-)(2A4MP+) (1), (pCA̶ )(2A6MP+) (2) and (TFA̶ )(2A4MP+)·( 3 2 H2O) (3). For salt 3, water was included in the crystal structure fulfilling a bridging role. pCA formed a 1:1 salt with 2A4MP (Z' = 1) and a 4:4 salt with 2A6MP (Z' = 4). The thermal stability of the salts was determined using differential scanning calorimetry (DSC). Salt 2 had the highest thermal stability followed by salt 1 and salt 3. The salts were also characterised using Fourier transform infrared (FTIR) spectroscopy. Hirshfeld surface analysis was used to study the different intermolecular interactions in the three salts. Solvent-assisted grinding was also investigated in attempts to reproduce the salts.

The decrease of some serum free amino acids can predict breast cancer diagnosis and progression.

This study was targeted on a metabolomic approach to compare the blood serum free amino acid profiles and concentration of confirmed breast cancer (stages I-III) patients to healthy controls in order to establish reliable biomarkers of early detection and prediction of breast cancer. The ultra-high-performance liquid chromatography coupled with mass spectrometry using positive ionization electrospray was applied for the picoline-derivatized serum free amino acids using the EZ:faastTM kit. Multivariate statistical analysis principal component analysis, partial least squares discrimination analysis and univariate analysis were applied in order to discriminate between patient groups and putative amino acid biomarkers for breast cancer. A significant decrease of amino acid concentrations between the breast cancer group and the control group was positively correlated with breast cancer progression. Arginine, Alanine, Isoleucine, Tyrosine and Tryptophan were identified as being good potential discriminants (AUROC ≥0.85) and suitable candidates to diagnose and predict the breast cancer progression.

Synthesis, characterization, and in vitro effect of the Cu(II) complex with niflumic acid and 3-picoline on paraoxanase-I.

Niflumic acid is used to treat inflammatory rheumatoid diseases, pain, and fever. The present study reports the experimental, spectroscopic, thermal, structural analyses, and biological activities of this complex. The nonsteroidal anti-inflammatory drug niflumic acid, 3-picoline, and copper(II) chloride were utilized to synthesize a new complex: [Cu2 Cl 2 (nif) 2 (3-pic) 4 ]. The crystal structure of [Cu 2 Cl 2 (nif) 2 (3-pic) 4 ] was determined by X-ray crystallography. The complex crystallizes in the triclinic space group P-1 and each Cu(II) center displayed six-coordinated distorted octahedral geometry. Two Cu(II) centers are connected by a chloro-bridge to form the binuclear metal core. Finally, the in vitro effects of the synthesized new complex and free niflumic acid were evaluated on the human serum paraoxonase 1 enzyme. At low doses, both the new complex and free niflumic acid showed very good inhibition activity with different inhibition mechanisms. In addition, the results showed that the new complex has more inhibition activity than free niflumic acid.

Membranotropic and Antiradical Properties of 2-Nitroxysuccinate 3-Hydroxy-6-Methyl-2-Ethylpyridine.

We studied membranotropic properties of NO donor 2-nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine and its structural analog succinate 3-hydroxy-6-methyl-2-ethylpyridine (Mexidol). It was shown that the compounds under study are incorporated into modeled membranes and form long-living complexes with pyrene in the region of fatty acid tails of phospholipids. Luminol-amplified chemiluminescence analysis showed that both compounds exhibited antiradical activity and in a concentration of 0.1 mM reduced chemiluminescence intensity by more than 70%. 2-Nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine inhibited catalytic activity of monoamine oxidase A more efficiently than its structural analogue Mexidol.

A New Ratiometric Lysosomal Copper(II) Fluorescent Probe To Map a Dynamic Metallome in Live Cells.

We synthesized a new ratiometric fluorescent Cu2+ probe, bearing a morpholine moiety for selective binding to lysosomes and two picolylamine arms for the specific chelation of divalent copper ions. The probe capability to detect lysosomal Cu2+ was demonstrated in human differentiated neuroblastoma cells by confocal microscopy.

A Diverse and Versatile Regiospecific Synthesis of Tetrasubstituted Alkylsulfanylimidazoles as p38α Mitogen-Activated Protein Kinase Inhibitors.

An alternative strategy for the synthesis of 1-aryl- and 1-alkyl-2-methylsulfanyl-4-(4-fluorophenyl)-5-(pyridin-4-yl)imidazoles as potential p38α mitogen-activated protein kinase inhibitors is reported. The regioselective N-substitution of the imidazole ring was achieved by treatment of α-aminoketones with different aryl or alkyl isothiocyanates. In contrast to previously published synthesis routes starting from 2-amino-4-methylpyridine, the presented route is characterized by a higher flexibility and a lower number of steps. This strategy was also applied to access 1-alkyl-2-methylsulfanyl-5-(4-fluorophenyl)-4-(pyridin-4-yl)imidazoles in six steps starting from 2-chloro-4-methylpyridine.

Experimental and Theoretical Study on the Synergistic Inhibition Effect of Pyridine Derivatives and Sulfur-Containing Compounds on the Corrosion of Carbon Steel in CO2-Saturated 3.5 wt.% NaCl Solution.

The corrosion inhibition performance of pyridine derivatives (4-methylpyridine and its quaternary ammonium salts) and sulfur-containing compounds (thiourea and mercaptoethanol) with different molar ratios on carbon steel in CO2-saturated 3.5 wt.% NaCl solution was investigated by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy, and scanning electron microscopy. The synergistic corrosion inhibition mechanism of mixed inhibitors was elucidated by the theoretical calculation and simulation. The molecules of pyridine derivative compounds with a larger volume has priority to adsorb on the metal surface, while the molecules of sulfur-containing compounds with a smaller volume fill in vacancies. A dense adsorption film would be formed when 4-PQ and sulfur-containing compounds are added at a proper mole ratio.

Non-Covalent Assembly Method that Simultaneously Endows a Liposome Surface with Targeting Ligands, Protective PEG Chains, and Deep-Red Fluorescence Reporter Groups.

A new self-assembly method is used to rapidly functionalize the surface of liposomes without perturbing the membrane integrity or causing leakage of the aqueous contents. The key molecule is a cholesterol-squaraine-PEG conjugate with three important structural elements: a cholesterol membrane anchor, a fluorescent squaraine docking station that allows rapid and high-affinity macrocycle threading, and a long PEG-2000 chain to provide steric shielding of the decorated liposome. The two-step method involves spontaneous insertion of the conjugate into the outer leaflet of pre-formed liposomes followed by squaraine threading with a tetralactam macrocycle that has appended targeting ligands. A macrocycle with six carboxylates permitted immobilization of intact fluorescent liposomes on the surface of cationic polymer beads, whereas a macrocycle with six zinc(II)-dipicolylamine units enabled selective targeting of anionic membranes, including agglutination of bacteria in the presence of human cells.

Discovery of potent and selective CDK8 inhibitors through FBDD approach.

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.

Antiplasmodial activity of targeted zinc(II)-dipicolylamine complexes.

This study measured the antiplasmodial activity of nine zinc-dipicolylamine (ZnDPA) complexes against three strains of Plasmodium falciparum, the causative parasite of malaria. Growth inhibition assays showed significant activity against all tested strains, with 50% inhibitory concentrations between 5 and 600nM and almost no toxic effect against host cells including healthy red blood cells. Fluorescence microscopy studies with a green-fluorescent ZnDPA probe showed selective targeting of infected red blood cells. The results suggest that ZnDPA coordination complexes are promising antiplasmodial agents with potential for targeted malaria treatment.

New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation.

Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki=0.046nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki=0.0224nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki=0.8nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.

Distal-Bond-Selective C-C Activation of Ring-Fused Cyclopentanones: An Efficient Access to Spiroindanones.

A site-selective rhodium-catalyzed C-C activation of ring-fused cyclopentanones was achieved to afford efficient access to a range of spiroindanones. The use of bulky 2-amino-6-picoline as a cocatalyst is key to the excellent selectivity of this C-C bond cleavage in cyclopentanones.

Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile.

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.

This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).

2,3-Di-O-picolinyl building blocks as glycosyl donors with switchable stereoselectivity.

2-O-Picolinyl protected glycosyl donors lead to the formation of 1,2-trans glycosides with complete stereoselectivity. This is due to the participatory effect of the picolinyl nitrogen that is able to block the bottom face of the ring via a six-membered cyclic intermediate. Herein we demonstrate that if the nitrogen atom of the O-picolinyl moiety is temporarily blocked by coordination to the metal center (Pd), it becomes unavailable to participate in glycosylation and hence the stereoselectivity of 2-O-picolinyl-assisted glycosylations can be "switched".

[DYNAMICS OF BACTERIOLOGICAL AND PLANIMETRIC INDICES OF THE WOUND UNDER THE ACTION OF THE SILVER NANOPARTICLES, STABILIZED BY MEXIDOL AND POLYVINYLPYRROLIDONE].

Changes in bacteriological indices through the square of the wound of chemical origin under local impact of the silver nanoparticles (NP), stabilized by 2-ethyl-6-methyl-3-hydroxypyridine succinate (mexidol) and polyvinylpyrrolidone were studied. The wounds of submandibular region were simulated in white rats, using injection of 10% solution of calcium chloride with further opening of necrotic foci and open management of the wound. Beginning from the fifth day, every day the wound was irrigated with liquid, which have contented the stabilized NP of the silver, 0.05% water solution of chlorhexidine or isotonic solution of the the sodium chloride (control). There was established, that the silver NP impact antiseptically and regenerative while the wound treatment, and reduce during 10 days microbial contamination of exudate in 24 times, the wound square--in three times in comparison with original indices. These changes were identical to those while application of chlorhexidine.

Room-temperature transition-metal-free one-pot synthesis of 3-aryl imidazo[1,2-a]pyridines via iodo-hemiaminal intermediate.

A mild and efficient one-pot synthesis of 3-aryl imidazo[1,2-a]pyridines in up to 88% yield was developed. An adduct was formed after the simple mixing of 2-amino-4-methylpyridine, 2-phenylacetaldehyde, and N-iodosuccinimide in CH2Cl2, and the structure of the adduct was characterized by 2D NMR, IR, and high-resolution mass analysis. The adduct was readily cyclized by treatment with a saturated aqueous solution of NaHCO3. The reactions proceeded to completion after several hours at room temperature.

Bacterial imaging and photodynamic inactivation using zinc(II)-dipicolylamine BODIPY conjugates.

Targeted imaging and antimicrobial photodynamic inactivation (PDI) are emerging methods for detecting and eradicating pathogenic microorganisms. This study describes two structurally related optical probes that are conjugates of a zinc(II)-dipicolylamine targeting unit and a BODIPY chromophore. One probe is a microbial targeted fluorescent imaging agent, mSeek, and the other is an oxygen photosensitizing analogue, mDestroy. The conjugates exhibited high fluorescence quantum yield and singlet oxygen production, respectively. Fluorescence imaging and detection studies examined four bacterial strains: E. coli, S. aureus, K. pneumonia, and B. thuringiensis vegetative cells and purified spores. The fluorescent probe, mSeek, is not phototoxic and enabled detection of all tested bacteria at concentrations of ∼100 CFU mL(-1) for B. thuringiensis spores, ∼1000 CFU mL(-1) for S. aureus and ∼10,000 CFU mL(-1) for E. coli. The photosensitizer analogue, mDestroy, inactivated 99-99.99% of bacterial samples and selectively killed bacterial cells in the presence of mammalian cells. However, mDestroy was ineffective against B. thuringiensis spores. Together, the results demonstrate a new two-probe strategy to optimize PDI of bacterial infection/contamination.

Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability.

In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu4 have been developed. To better understand the role of mGlu4 in healthy and disease conditions, we are interested in developing an mGlu4 selective radioligand for in vivo studies. Thus, we had synthesized and studied [(11)C]2 as a PET tracer for mGlu4, which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu4 ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu4. The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu4 ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability.

Unusual Example of Chelate Ring Opening upon Coordination of the 9-Ethylguanine Nucleobase to [Pt(di-(6-methyl-2-picolyl)amine)Cl]Cl.

Anticancer-active monofunctional Pt(II) complexes have bulky carrier ligands and bind to G residues in DNA, causing structural distortions. To gain fundamental chemical information on such monofunctional adducts, we assessed the 9-ethylguanine (9-EtG) adducts formed by [Pt(N(H)6,6'-Me2dpa)Cl]Cl (N(H)6,6'-Me2dpa = di-(6-methyl-2-picolyl)amine). 9-EtG added to [Pt(N(H)6,6'-Me2dpa)Cl]Cl to form not only the expected [Pt(N(H)6,6'-Me2dpa)(9-EtG)](2+) monoadduct having syn and anti conformers but also a [Pt(N(H)6,6'-Me2dpa)(9-EtG)2](2+) bisadduct consisting of ΛHT and ΔHT conformers (HT = head-to-tail). For both adducts, the two conformers exist as a dynamic equilibrium mixture. Concomitant with formation of the bisadduct, the binding mode of the N(H)6,6'-Me2dpa ligand converts from tridentate to bidentate. A Pt(II)-bound 6-methyl-2-picolyl chain and the secondary amine constitute the bidentate chelate ring. The other 6-methyl-2-picolyl chain is dangling. The secondary nitrogen is an asymmetric center, and each conformer exists as a racemic mixture of two enantiomers. For a given configuration at the secondary amine of the [Pt(N(H)6,6'-Me2dpa)(9-EtG)2](2+) adduct, the more abundant HT conformer can form a hydrogen bond between the NH of the bidentate ligand and the cis 9-EtG O6. [Pt(N(H)6,6'-Me2dpa)Cl]Cl forms the monoadduct in ∼1/20 the time for its parent, [Pt(N(H)dpa)Cl]Cl (N(H)dpa = di(2-picolyl)amine), which exhibited typical behavior in forming only a monoadduct. We attribute the unusual new findings for [Pt(N(H)6,6'-Me2dpa)Cl]Cl to Pt-N bond weakening induced by the steric bulk of 6/6'-Me groups. We hypothesize that undetectable intermediates with a dangling 6-methyl-2-picolyl chain facilitate both rapid monoadduct formation and also bisadduct formation. Consistent with the intermediacy of such species with a dangling chain, addition of HCl to a [Pt(N(H)6,6'-Me2dpa)Cl]Cl solution readily produced a dichloro complex with the N(H)6,6'-Me2dpa chelate ligand in the bidentate mode, whereas HCl addition had no effect on [Pt(N(H)dpa)Cl]Cl.