A novel 2-(2-aminophenyl) imidazo [1,5-a] pyridine-based fluorescent probe for rapid detection of phosgene.

Phosgene is a highly concealed and highly toxic gas that seriously threatens human health and public security. Therefore, the detection of phosgene is of great significance to world security. Herein, a new type of fluorescent probe based on 2-(2-aminophenyl) imidazo [1,5-a] pyridine is reported for the rapid detection of phosgene. The probe itself only emits a faint green fluorescence, while phosgene allows it to produce a strong blue fluorescence. During the recognition process, phosgene interacts simultaneously with both amino site and imidazole moiety in the probe molecule, resulting in a four-ring-fused rigid structure with high fluorescence quantum yield. The probe not only has the characteristics of high efficiency, high sensitivity (detection limit 2.68 nM), and high selectivity, but also has remarkable spectral changes. Finally, a portable test strip is used to detect phosgene in the gas phase, and the fluorescent color change of the test strip can be easily observed. The most exciting thing is that the portable test strip with the probe PMPY-NH2 can produce a strong fluorescence response to 1 ppm of phosgene, which is far lower than the level of phosgene that seriously threatens to human health.

One-Dimensional and Two-Dimensional Zn(II) Coordination Polymers with Ditopic Imidazo[1,5-a]pyridine: A Structural and Computational Study.

Zn(II) coordination polymers are being increasingly studied for their stability and properties. Similarly, there is a growing interest in imidazo[1,5-a]pyridine derivatives, which show great potential in luminescence and pharmaceutical applications. In this work, we successfully synthesized and crystallized three new coordination polymers, using Zn(II) as the metallic node, dicarboxylic acids of different length and nature as linkers, and a linear ditopic imidazo[1,5-a]pyridine derivative, to explore the role of this molecule as a propagator of the dimensionality of the structure or as an ancillary ligand. Our work demonstrates the structural capability of imidazo[1,5-a]pyridines in an unexplored domain for this family of ligands. Notably, we observed a pronounced ability of this heterocyclic scaffold to establish π···π interactions in the solid state. The supramolecular π-stacked assemblies were theoretically analyzed using DFT calculations based on model structures.

Mono-, Bis-, and Tris-Chelate Zn(II) Complexes with Imidazo[1,5-a]pyridine: Luminescence and Structural Dependence.

New mono-, bis-, and tris-chelate Zn(II) complexes have been synthesized starting from different Zn(II) salts and employing a fluorescent 1,3-substituted-imidazo[1,5-a]pyridine as a chelating ligand. The products have been characterized by single-crystal X-ray diffraction; mass spectrometry; and vibrational spectroscopy. The optical properties have been investigated to compare the performances of mono-, bis-, and tris-chelate forms. The collected data (in the solid state and in solution) elucidate an important modification of the ligand conformation upon metal coordination; which is responsible for a notable increase in the optical performance. An intense modification of the emission quantum yield along the series in the solid state is observed comparing mono-, bis-, and tris-chelate adducts; independently from the anionic ligand introduced by ionic exchange.

Imidazo[1,5-a]pyridine-Based Fluorescent Probes: A Photophysical Investigation in Liposome Models.

Imidazo[1,5-a]pyridine is a stable scaffold, widely used for the development of emissive compounds in many application fields (e.g., optoelectronics, coordination chemistry, sensors, chemical biology). Their compact shape along with remarkable photophysical properties make them suitable candidates as cell membrane probes. The study of the membrane dynamics, hydration, and fluidity is of importance to monitor the cellular health and to explore crucial biochemical pathways. In this context, five imidazo[1,5-a]pyridine-based fluorophores were synthesized according to a one-pot cyclization between an aromatic ketone and benzaldehyde in the presence of ammonium acetate and acetic acid. The photophysical features of prepared compounds were investigated in several organic solvents and probes 2-4 exhibited the greatest solvatochromic behavior, resulting in a higher suitability as membrane probes. Their interaction with liposomes as artificial membrane model was tested showing a successful intercalation of the probes in the lipid bilayer. Kinetic experiments were carried out and the lipidic phase influence on the photophysical features was evaluated through temperature-dependent experiments. The results herein reported encourage further investigations on the use of imidazo[1,5-a]pyridine scaffold as fluorescent membrane probes.

Discovery of Novel Imidazopyridine GSK-3ß Inhibitors Supported by Computational Approaches.

The interest of research groups and pharmaceutical companies to discover novel GSK-3ß inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives 1-6, showing good GSK-3ß inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability. Here, we describe the design, synthesis, and in vitro characterization of novel imidazo[1,5-a]pyridine-1-carboxamide (IMID 1) and imidazo[1,5-a]pyridine-3-carboxamide (IMID 2) compounds (7-18) to overcome such liability. In detail, structure-based approaches and fine-tuning of physicochemical properties guided the design of derivatives 7-18 resulting in ameliorated absorption, distribution, metabolism, and excretion (ADME) properties. A crystal structure of 16 in complex with GSK-3ß enzyme (PDB entry 6Y9S) confirmed the in silico models. Despite the nanomolar inhibition activity, the new core compounds showed a reduction in potency with respect to INDZ derivatives 1-6. In this context, Molecular Dynamics (MD) and Quantum Mechanics (QM) based approaches along with NMR investigation helped to rationalize the observed structure activity relationship (SAR). With these findings, the key role of the acidic hydrogen of the central core for a tight interaction within the ATP pocket of the enzyme reflecting in good GSK-3ß affinity was demonstrated.

An Imidazo[1,5-α]Pyridine-Based Fluorometric Chemodosimeter for the Highly Selective Detection of Hypochlorite in Aqueous Media.

A new fluorometric chemodosimeter 2-amino-3-(((E)-3-(1-phenylimidazo[1,5-α]pyridin-3-yl)benzylidene)amino)maleonitrile (BPI-MAL) has been designed and synthesized for sensing hypochlorite. BPI-MAL showed a selective turn-on fluorescence for ClO- through hypochlorite-promoted de-diaminomaleonitrile reaction. It also could detect ClO- in the presence of various competitive anions including reactive oxygen species. Interestingly, sensor BPI-MAL was successfully applied as a fluorescent test kit for ClO- determination. The sensing property and mechanism of BPI-MAL toward ClO- were studied by fluorescence and UV-vis spectroscopy, NMR titration and DFT calculations.

Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479.

Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi's [J. Med. Chem.2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem.2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem.2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450's 2C9 and 2C19. Lowering the logD by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.

Synthesis, crystal structure, optical properties and antibacterial evaluation of novel imidazo[1, 5-a]pyridine derivatives bearing a hydrazone moiety.

A series of novel imidazo[1,5-a]pyridine-hydrazone derivatives were synthesized and characterized by infrared spectroscopy (IR), 1H NMR, 13C NMR and high resolution mass spectrometer (HRMS). Typically, the spatial structure of compound 3j was determined using X-ray diffraction analysis. The UV-vis absorption and fluorescence spectral characteristics of the compounds in dichloromethane and acetonitrile were investigated. Absorption peaks could be observed in the wavelength range 290-450 nm. It can also be seen that they display very similar maximum emission. The group attached to hydrazone hardly influenced the maximum emission. Furthermore, all the compounds were evaluated for antibacterial activity and were found to be more effective against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa and Shigella compared with chloramphenicol.

Imidazopyridine-based selective and multifunctional ligands of biological targets associated with psychiatric and neurodegenerative diseases.

This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., ß-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H3, serotonin 5-HT3, 5-HT4, 5-HT6, dopamine D4, adenosine A2A, orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed.

Natural aldehyde extraction and direct preparation of new blue light-emitting imidazo[1,5-a]pyridine fluorophores.

This work describes the extraction of natural aldehydes and the use of extracts to synthesise new fluorescent imidazo[1,5-a]pyridine derivatives. The characterisation of the extracted aldehydes by different techniques and the optical study of the fluorescent products allow the design of new compounds suitable for pharmaceutical, down-shifting, microscopy and electronic applications. The fluorophores are generated by an easy one-pot cyclisation reaction in mild conditions without catalyst and with only water as by-product.

The synthesis, characterization and optical properties of novel 5-(3-aryl-1H-pyrazol-5-yl)-2-(3-butyl-1-chloroimidazo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole.

A series of novel 5-(3-aryl-1H-pyrazol-5-yl)-2-(3-butyl-1-chloroimidazo[1,5-a]- pyridin-7-yl)-1,3,4-oxadiazole derivatives has been synthesized from 3-butyl-1-chloroimidazo[1,5-a]pyridine-7-carboxylic acid and ethyl 3-aryl-1H-pyrazole-5-carboxylate. The compounds were characterized using IR, (1)H NMR, HRMS and UV-vis absorption. The fluorescence spectral characteristics of the compounds in dichloromethane were investigated. The results showed that absorption λmax and emission λmax was less correlated with substituent groups on N-1 position of pyrazole moiety and para position of benzene moiety. The calculated molecular orbital correlates well with their absorption.