Pyridine Head Research Articles

Synthesis and evaluation of phenylimidazole FabK inhibitors as new Anti-C. Difficile agents

Previously, 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(5-(pyridin-2-ylthio)thiazol-2-yl)urea bearing a p-bromine substitution was shown to possess selective inhibitory activity against the Clostridioides difficile enoyl-acyl carrier protein (ACP) reductase II enzyme, FabK. Inhibition of CdFabK by this compound translated to promising antibacterial activity in the low micromolar range. In these studies, we sought to expand our knowledge of the SAR of the phenylimidazole CdFabK inhibitor series while improving the potency of the compounds. Three main series of compounds were synthesized and evaluated based on: 1) pyridine head group modifications including the replacement with a benzothiazole moiety, 2) linker explorations, and 3) phenylimidazole tail group modifications. Overall, improvement in the CdFabK inhibition was achieved, while maintaining the whole cell antibacterial activity. Specifically, compounds 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(5-((3-(trifluoromethyl)pyridin-2-yl)thio)thiazol-2-yl)urea, 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)urea, and 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(6-chlorobenzo[d]thiazol-2-yl)urea showed CdFabK inhibition (IC50 = 0.10 to 0.24 μM), a 5 to 10-fold improvement in biochemical activity relative to 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(5-(pyridin-2-ylthio)thiazol-2-yl)urea, with anti-C. difficile activity ranging from 1.56 to 6.25 μg/mL. Detailed analysis of the expanded SAR, supported by computational analysis, is presented.

Mitochondrial targeted fluorescent nitrite peroxide probe for dynamic monitoring of cellular lung injury

Herein, a mitochondrial targeted fluorescent nitrite peroxide probe CHP for dynamic monitoring of cellular lung injury was developed. For the practical delivery and selectivity, the structural features including pyridine head and borate recognition group were selected. CHP could respond to ONOO− with the 585 nm fluorescence signal. The detecting system indicated advantages such as wide linear range (0.0–30 μM), high sensitivity (LOD = 0.18 μM), high selectivity and steadiness under different environmental conditions including pH (3.0–10.0), time (48 h) and medium. In living A549 cells, the response of CHP towards ONOO− showed dose-dependent and time-dependent tendencies. The co-localization suggested that CHP could achieve mitochondrial targeting. Moreover, CHP could monitor the variation of endogenous ONOO− level and the cellular lung injury induced by LPS.

Divergent synthesis and biological evaluation of 2-(trifluoromethyl)pyridines as virulence-attenuating inverse agonists targeting PqsR

A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.

Exchange Speed of Four-Component Nanorotors Correlates with Hammett Substituent Constants

Three distinct four-component supramolecular nanorotors were prepared, using, for the first time, bipyridine instead of phenanthroline stations in the stator. Following our established self-sorting protocol to multicomponent nanodevices, the nanorotors were self-assembled by mixing the stator, rotators with various pyridine head groups, copper(I) ions and 1,4-diazabicyclo[2.2.2]octane (DABCO). Whereas the exchange of a phenanthroline vs. a bipyridine station did not entail significant changes in the rotational exchange frequency, the para-substituents at the pyridine head group of the rotator had drastic consequences on the speed: 4-OMe (k298 = 35 kHz), 4-H (k298 = 77 kHz) and 4-NO2 (k298 = 843 kHz). The exchange frequency (log k) showed an excellent linear correlation with both the Hammett substituent constants and log K of the copper(I)–ligand interaction, proving that rotator–copper(I) bond cleavage is the key determining factor in the rate-determining step.

Pyridine-based chiral smectogens: effects of polar end groups on liquid crystal properties

ABSTRACT In this study, novel chiral pyridine-based rod-like mesogens, consisting of a chloro or bromo group substituted pyridine head core which is connected to one or two aromatic rings through ester linkers and a flexible (S)-2-methylbutoxy or (S)-3,7-dimethyloctyloxy chiral end chain have been synthesised. The liquid crystal properties of new compounds were investigated by various experimental techniques such as DSC, POM and SAXS. Depending of the nature of the halogen end group, the derivatives with two aromatic rings are non-mesogenic compounds whereas a smectic A phase (SmA) enantiotropically occurs for the members with three aromatic rings of the series. Additionally, chloro group substituted compound composed of three aromatic rings carrying a (S)-2-methylbutoxy end chain exhibits an enantiotropic chiral nematic phase (N*).

Derivatives of 3-Amino-2-methylpyridine as BAZ2B Bromodomain Ligands: In Silico Discovery and in Crystallo Validation.

The 3-amino-2-methylpyridine derivative 1 was identified as ligand of the BAZ2B bromodomain by automatic docking of nearly 500 compounds, selected on the basis of previous fragment hits. Hit expansion by two in silico approaches, pharmacophore search followed by docking, and substructure search resulted in five additional ligands. The predicted binding mode of the six 3-amino-2-methylpyridine derivatives was validated by protein crystallography. A small displacement of residues 1894-1899 of the ZA loop is observed for two of the six ligands. In all structures, the pyridine head is involved in a water-mediated hydrogen bond with the side chain of the conserved Tyr1901 while the 3-amino linker acts as hydrogen bond donor for the backbone carbonyl of Pro1888. Heterogeneous orientations are observed for the tail groups (i.e., the 3-amino substituents). The sulfonyl group in the tail of compounds 1 and 2 is involved in a hydrogen bond with the backbone amide of Asn1894.

Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.

1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation

Simultaneous targeting of dopamine D2 and 5-HT2A receptors for the treatment of schizophrenia is one key feature of typical and atypical antipsychotics. In most of the top-selling antipsychotic drugs like aripiprazole and risperidone, high affinity to both receptors can be attributed to the presence of 1,4-disubstituted aromatic piperazines or piperidines as primary receptor recognition elements. Taking advantage of our in-house library of phenylpiperazine-derived dopamine receptor ligands and experimental data, we established highly significant CoMFA and CoMSIA models for the prediction of 5-HT2A over D2 selectivity. Subsequently, the models were applied to identify the selective candidates 55–57 from our newly synthesized library of GPCR ligands comprising a pyrazolo[1,5-a]pyridine head group and a 1,2,3-triazole based linker unit. The test compound 57 showed subnanomolar a Ki value (0.64nM) for 5-HT2A and more than 10- and 30-fold selectivity over the dopamine receptor isoforms D2S and D2L, respectively.

Lead(II) Complexes of Lateral Macrobicyclic Receptors That Incorporate a Crown Moiety and a Pyridine Head Unit

The coordinative properties towardslead(II) of two lateral macrobicyclic receptors that incorporate either a 1,10-diaza-[15]crown-5 (L7) or a 4,13-diaza-[18]crown-6 (L8) fragment are reported. Their protonation constants as well as the stability constants of their PbII complexes have been investigated by using potentiometric titrations.

A divergent synthesis of oligoarylalkanethiols with Lewis-basic N-donor termini

Araliphatic thiols are key molecules for the formation of self-assembled monolayers with high long-range order. If these monolayers shall act as bases for the attachment of other molecules, the respective thiols need to carry suitable functional groups, such as the amino or the pyridine group. Due to their Lewis-basicity, these groups are not compatible with the thiol group under most reaction conditions. Here, an entry into this versatile class of compounds is presented, by using fundamental building blocks in which the thiol groups are protected as triisopropylsilyl sulfides making them compatible with many reagents including Grignard reagents and palladium catalysts. With this strategy at hand, six thiols with bi- and terphenyl backbones, one to three methylene groups, and amino or pyridine head groups became accessible in short reaction sequences.

Solid‐State and Solution Structure of Lanthanide(III) Complexes with a Flexible Py‐N6 Macrocyclic Ligand

AbstractLanthanide complexes of a hexaaza macrocyclic ligand containing a pyridine head unit (L) were synthesized (Ln = La–Lu, except Pm). The solid‐state structures of the corresponding La, Ce, Pr, Nd, and Lu complexes were determined by single‐crystal X‐ray crystallography, and they reveal the presence of three different mononuclear complexes with three different conformations of the macrocycle and coordination environments around the metal ions. In all complexes the lanthanide ion is coordinated in an endomacrocyclic manner to the six nitrogen donor atoms of the ligand. In the La, Ce, and Pr complexes the metal ions show a 12‐coordinate mononuclear environment in which 3 nitrate anions coordinate in a bidentate fashion. However, in the Nd analogue the metal ion displays a 10‐coordinated environment with the coordination of 2 bidentate nitrate groups, whereas Lu shows a 9‐coordinate environment interacting with 2 nitrate ligands, one of them acting as bidentate and the second one coordinating in a monodentate fashion. The 1H and 13C NMR spectra of the complexes recorded in CD3CN suggest that the complexes adopt in solution a similar structure to that observed for the Nd complex in the solid state. The [Ln(L)(NO3)3] and [Ln(L)(NO3)2]+ complexes were characterized by density functional theory (DFT) calculations (B3LYP model). The structures obtained from these calculations for La, Ce, Pr, and Nd are in good agreement with the experimental solid‐state structures. The relative stabilities of the [Ln(L)(NO3)2]+ complexes with respect to the [Ln(L)(NO3)3] ones (Ln = La, Nd, Gd, Ho, or Lu) were studied both in vacuo and in acetonitrile solution (PCM model) at the same computational level. Our calculations indicate that in solution the [Ln(L)(NO3)2]+ species is the most stable one along the whole lanthanide series, in agreement with the NMR spectroscopic data.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Protonated Macrobicyclic Hosts Containing Pyridine Head Units for Anion Recognition

In this paper, we report two macrobicyclic receptors containing pyridine head units derived from 1,10-diaza-15-crown[5] (L1) or 4,13-diaza-18-crown[6] (L2) that can be protonated in MeCN and used for anion recognition. The interaction of these protonated lateral macrobicycles with different anions has been investigated by means of spectrophotometric titrations in MeCN. The association constants for the complexes of halide anions with the protonated macrobicycles follow the sequences Cl(-)>Br(-)>I(-)>F(-) (L1) and Cl(-)>F(-)>I(-)>Br(-) (L2), whereby an increase of more than two logarithmic units is observed from F(-) to Cl(-) for the binding constants of the receptor derived from L1. The association constants also indicate an important degree of selectivity of these macrobicyclic receptors for Cl(-) over Br(-) or I(-). The X-ray crystal structure analyses of the chloride and bromide complexes confirms the formation of the envisaged supramolecular complexes. Moreover, the binding constants indicate that these receptors present a high sulfate-to-nitrate binding selectivity. The stability trend observed for the recognition of halide anions by the macrobicycles presented herein as well as the sulfate-to-nitrate binding selectivity have been rationalised by means of DFT calculations at the B3LYP/LanL2DZ level. These studies indicate that the especially high binding selectivity for Cl(-) is the result of the optimum fit between the protonated macrobicyclic cavity and the size of the anion, whereas the sulfate-to-nitrate selectivity results from shape complementarity between the hydrogen-binding acceptor sites on sulfate and the hydrogen-bond donors of the macrobicycle.

Reversible Photoswitchable Wettability in Noncovalently Assembled Multilayered Films

Reversible and irreversible photoinduced changes in surface wettability were observed in noncovalently assembled multilayered films. The multilayered films studied were fabricated from a self-assembled monolayer (SAM) consisting of 4-(10-mercaptodecyloxy)pyridine-2,6-dicarboxylic acid on gold, Cu(II) ions complexed to the pyridine head group of the SAM, and either cis- (film 1) or trans- (film 2) stilbene-4,4'-dicarboxylic acid complexed to the Cu(II) ions. Irradiation of film 1 at wavelengths corresponding to the absorption band of the cis-stilbene isomer resulted in an irreversible chemical change and an irreversible increase in wettability, as indicated by surface contact angle and grazing incidence IR measurements. However, no evidence for cis-/trans-photoisomerization was observed. Films 3 and 4, similar to films 1 and 2 in that they consist of an underlying SAM, an intermediate layer consisting of Cu(II) ions, and either cis- or trans-stilbene-4,4'-dicarboxylic acid as the capping ligand, were fabricated with a mixed SAM that contained both 4-(10-mercaptodecyloxy)pyridine-2,6-dicarboxylic acid and 4-tert-butylbenzenethiol. Irradiation of these films at wavelengths corresponding to stilbene isomer absorption bands resulted in reversible cis- to trans- (film 3) and trans- to cis- (film 4) photoisomerization and reversible switching of the surface wettability between a low wetting state (cis-stilbene) and a high wetting state (trans-stilbene). The difference in observed behavior between films 1 and 2 and films 3 and 4 is attributed to the greater surface spacing afforded by the mixed monolayer, which allows greater conformational flexibility and lowers the steric barriers to isomerization.

Assembly of Hexamolybdenum Metallic Clusters on Silicon Surfaces

Becoming attached: Mo6Ii8 (Ii=inner iodine) cluster cores are anchored in apical positions to monocrystalline silicon surfaces. The attachment occurs via pyridine groups, end-capping an alkyl monolayer which is covalently bound to the hydrogen-terminated silicon surface. Octahedral Mo6 clusters: orange; pyridine head groups of the monolayer: green; apical pyridine units: blue.

Synthesis, structural characterization and electrochemical studies of new macrocyclic Schiff base containing pyridine head and its metal complexes

A new macrocyclic ligand, 1,3,5-triaza-2,4:7,8:13,14-tribenzo-9,12-dioksa-cyclopentadeca-1,5-diene was synthesized by reaction of 2,6-diaminopyridine and 1,2-bis(2-carboxyaldehyde phenoxy)ethane. Then, its Cu(II), Ni(II), Pb(II), Co(III) and La(III) complexes were synthesized by the template effect by the reaction of 2,6-diaminopyridine and 1,2-bis(2-carboxyaldehyde phenoxy)ethane and Cu(NO 3) 2 · 3H 2O, Ni(NO 3) 2 · 6H 2O, Pb(NO 3) 2, Co(NO 3) 2 · 6H 2O, La(NO 3) 3 · 6H 2O, respectively. The ligand and its metal complexes have been characterized by elemental analysis, IR, 1H and 13C NMR, UV–Vis spectra, magnetic susceptibility, thermal gravimetric analysis, conductivity measurements, mass spectra, and cyclic voltammetry. All complexes are diamagnetic and Cu(II) complex is binuclear. The Co(II) was oxidized to Co(III). The comparative electrochemical studies show that the nickel complex exhibited a quasi-reversible one-electron reduction process, while copper and cobalt complexes gave irreversible reduction processes in DMSO solution.

Lanthanide(III) complexes with pyridine head macrocyclic ligands

The ability of lanthanide(III) ions to form stable complexeswith three different macrocyclic ligands, L1 , L2 and L3 , has been investigated.The Schiff base macrocycle L1 and its corresponding reduced ligand L2 arederived from 2,6-bis(2-formylphenoxymethyl)pyridine and diethylentriamine;the reduced ligand L3 is derived from 2,6-diformylpyridine and N,N-bis(3-aminopropyl)methylamine. Lanthanide nitrate complexes of L1 and L2 have beenprepared by direct reaction between each ligand and the appropriate hydrated lanthanidenitrate; attempts to obtain the corresponding perchlorate complexes have been unsuccessful.All nitrate complexes of L1 give the expected [1:1, Ln:L1 ] stoichiometry; however, complexes obtained with L2 show a [2:1, Ln:L2 ] stoichiometry. Finally, complexation reactions with L3 have been carried out in order to investigatethe coordination capability of this small and flexible ligand towards the Ln(III) ions.

Multi-Site Binding of Aqueous Dipeptides by Mixed Monolayers at the Air-Water Interface

Abstract Aqueous dipeptides are bound to two-component monolayers which contain oligopeptide polar units together with benzoic acid or pyridine head groups. Binding of guest dipeptides to the mixed monolayers depends specifically on the nature of interfacial cavities which can be controlled by combination of polar head groups. The binding ratio is lessened with increasing sizes of the side chain of the Y residue in the Gly-Y dipeptide moiety of the host amphiphiles.

Synthesis of a new unsymmetrical trinucleating macrocycle incorporating both phenolic and pyridine head units: x-ray crystal structure of {[Pb2(L1)(Cl)](ClO4)2} x

Dilead(II) and tricopper(II) complexes of the new Unsymmetrical macrocycle L1– are prepared; the structure of the chloride-bridged chain polymer {[Pb2(L1)(Cl)](ClO4)2}x, 1, is described.