Pyridyl Urea Research Articles

Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas.

A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N'-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.

The metal- and column-free synthesis of pyridin-2-yl ureas carrying cyclic secondary amine substituents and establishing the mechanism of the reactions through a computational study

Pyridyl ureas as potential ASK1 inhibitors were synthesized through auto-tandem rearrangement and subsequent one-pot aminolysis involving a more accessible concerted pathway.

Discovery of pyridyl urea sulfonamide inhibitors of NaV1.7

NaV1.7 is an actively pursued, genetically validated, target for pain. Recently reported quinolinone sulfonamide inhibitors displayed promising selectivity profiles as well as efficacy in preclinical pain models; however, concerns about off-target liabilities associated with this series resulted in an effort to reduce the lipophilicity of these compounds. Successful prosecution of this strategy was challenging due to the opposing requirement for lipophilic inhibitors for NaV1.7 potency and in vivo clearance (CL). Deconstruction of the heterocyclic core of the quinolinone series and utilization of an intramolecular hydrogen bond to mimic the requisite pharmacophore enabled the introduction of polarity without adversely impacting CL. Ultimately, this strategy led to the identification of compound 29, which demonstrated favorable ADME and was efficacious in pre-clinical models of pain.

Anti-Proliferative and Cytoprotective Activity of Aryl Carbamate and Aryl Urea Derivatives with Alkyl Groups and Chlorine as Substituents.

Natural cytokinines are a promising group of cytoprotective and anti-tumor agents. In this research, we synthesized a set of aryl carbamate, pyridyl urea, and aryl urea cytokinine analogs with alkyl and chlorine substitutions and tested their antiproliferative activity in MDA-MB-231, A-375, and U-87 MG cell lines, and cytoprotective properties in H2O2 and CoCl2 models. Aryl carbamates with the oxamate moiety were selectively anti-proliferative for the cancer cell lines tested, while the aryl ureas were inactive. In the cytoprotection studies, the same aryl carbamates were able to counteract the CoCl2 cytotoxicity by 3–8%. The possible molecular targets of the aryl carbamates during the anti-proliferative action were the adenosine A2 receptor and CDK2. The obtained results are promising for the development of novel anti-cancer therapeutics.

Making and Breaking of Gels: Stimuli-Responsive Properties of Bis(Pyridyl-N-oxide Urea) Gelators.

The structural modification of existing supramolecular architecture is an efficient strategy to design and synthesize supramolecular gels with tunable and predictable properties. In this work, we have modified bis(pyridyl urea) compounds with different linkers, namely hexylene and butylene, to their corresponding bis(pyridyl-N-oxide urea). The gelation properties of both the parent and the modified compounds were studied, and the results indicated that modification of the 3-pyridyl moieties to the corresponding 3-pyridyl-N-oxides induced hydrogelation. The stability of the parent and modified compounds were evaluated by sol-gel transition temperature (Tgel) and rheological measurements, and single-crystal X-ray diffraction was used to analyze the solid-state interactions of the gelators. The morphologies of the dried gels were analyzed by scanning electron microscopy (SEM), which revealed that the structural modification did not induce any prominent effect on the gel morphology. The stimuli-responsive behavior of these gels in the presence of salts in DMSO/water was evaluated by rheological experiments, which indicated that the modified compounds displayed enhanced gel strength in most cases. However, the gel network collapsed in the presence of the chloride salts of aluminum(III), zinc(II), copper(II), and cadmium(II). The mechanical strength of the parent gels decreased in the presence of salts, indicating that the structural modification resulted in robust gels in most cases. The modified compounds formed gels below minimum gel concentration in the presence of various salts, indicating salt-induced gelation. These results show the making and breaking ability of the gel network in the presence of external stimuli (salts), which explains the potential of using LMWGs based on N-oxide moieties as stimuli-responsive materials.

Synthesis, Characterisation and Crystal Structure of a Novel Pyridyl Urea Macrocycle

A novel pyridyl urea based macrocycle has been synthesised and fully characterised including a single crystal X-ray structure determination. The synthetic approach first involves the reaction of benzyloxycarbonylaminopropyl-3-isocyanate with t-butyl 2-[(2-aminopyridin-3-yl)oxy]acetate resulting in a coupling product. After deprotection of the amine and acid moieties and coupling subsequent coupling in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a macrocycle is formed. The structures of the compounds were confirmed by mass spectrometry and NMR spectroscopy. The X-ray crystal structure of the macrocycle reveals as expected a non-binding conformation with an intramolecular hydrogen bond between the urea NH and the pyridyl nitrogen.

1604278: Synthesis, characterisation and crystal structure of a novel pyridyl urea macrocycle – ESI

1604278: Synthesis, characterisation and crystal structure of a novel pyridyl urea macrocycle – ESI

Substituent effect of N‐aryl‐N′‐pyridyl ureas as thermal latent initiators on ring‐opening polymerization of epoxide

ABSTRACTA series of N‐aryl‐N′‐pyridyl ureas were synthesized by the reactions of 4‐aminopyridine (4AP) with the corresponding isocyanates such as phenyl isocyanate, 4‐methylphenyl isocyanate, 4‐methoxyphenyl isocyanate, 4‐chlorophenyl isocyanate, 4‐(trifluoromethyl)phenyl isocyanate, and 4‐nitrophenyl isocyanate. Bulk polymerization of diglycidyl ether of bisphenol A (DGEBA) in the presence of the ureas as initiators was evaluated by differential scanning calorimetry (DSC) at a heating rate of 10 °C/min. The resulting DSC profiles indicated exothermic peaks above 140 °C, while the DSC profile measured for a formulation composed of DGEBA and pristine 4AP indicated an exothermic peak at around 120 °C, implying that the derivation of 4AP into the corresponding ureas is a useful strategy to achieve thermal latency. The peak top temperatures were correlated with the electron density of the aromatic ring of the ureas, that is, as the electron‐withdrawing nature of the substituent on the aromatic ring became larger, the peak increases. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2569–2574

Naphthalene linked pyridyl urea as a supramolecular gelator: a new insight into naked eye detection of I−in the gel state with semiconducting behaviour

The gelation and anion responsive behavior of some 3-aminopyridinium-based molecules1–5have been examined. Compound2shows naked eye detection of I−in the gel state.

Supramolecular pyridyl urea gels as soft matter with antibacterial properties against MRSA and/or E. coli.

The synthesis and characterisation of novel aryl-pyridyl ureas are described, which form self-assembly structures via extended hydrogen bonding and π-π interactions in the solid state, and in selected cases, form supramolecular gels with antimicrobial properties against Staphylococcus aureus and/or Escherichia coli.

Triggered formation of thixotropic hydrogels by balancing competitive supramolecular synthons

Two component hydrogels have been obtained by formation of 1 : 1 complexes of bis(pyridyl urea)s with a range of dicarboxylic acids. The gels are thixotropic and undergo an assembly process in which short segments can reversibly assemble into an interconnected fibrous network. NMR and IR spectroscopic data suggest that the gelators form neutral gelator–acid complexes rather than salts. The use of dicarboxylic acids to trigger gelation in bis(pyridyl urea)s parallels analogous triggered gelation of metal ions and halogen bond donors in related systems.

Synthesis and Antibacterial Activities of Pleuromutilin Derivatives Containing Aryl Urea Groups

A series of novel pleuromutilin derivatives containing aryl urea groups was synthesized and their antibacterial activities were evaluated in vitro against S. aureus ATCC 26113, S.aureus SC, S. albus ATCC 8799 and P. aeruginosa ATCC 27853. Most of compounds exhibited more potent activities than reference drug tiamulin against S. aureus ATCC 26113 and S. aureus SC. Especially, compounds 12f and 12h containing pyridyl urea group and compound 12j with quinolinyl urea group showed excellent activity with the MIC value less than 0.001μg/ml against S. aureus SC. Keywords: Pleuromutilin; Derivatives; Aryl urea; Synthesis; Antibacterial activity.

Effect of coordinating (–CN) vs. non-coordinating (–F) substituents in 3-pyridyl urea receptors toward second sphere sulfate recognition: selective crystallisation of CuSO4 from mixtures of competing anions/cations

4-Fluorophenyl and 4-cyanophenyl substituted 3-pyridyl urea, L1111 and L2222 respectively, were synthesized and explored extensively to demonstrate SO42− binding via second sphere coordination in their respective self-assembled structures assisted by Cu2+, Cd2+ and Co2+. A single crystal X-ray diffraction study depicts second sphere SO42− recognition in the C4v symmetric cleft formed by the assembly of four molecules of the Cu2+ complex of L1111, [CuL11114(H2O)2]SO4, (1), via eight N–H⋯O interactions from four urea moieties. Similarly, second sphere SO42− recognition via twelve hydrogen bonding interactions (N–H⋯O and C–H⋯O) is also demonstrated in the assembly of the Cd2+ complex of L1111 i.e. [CdL11114(H2O)2]SO4, (2). Detailed structural analysis of 1 and 2 shows the formation of the coordination complexes of Cu2+ and Cd2+ with four units of pyridyl urea, which further assemble to generate a suitable coordination environment for the recognition of SO42− via second sphere coordination. On the other hand, L2222 with a coordinating substituent shows second sphere SO42− coordination with eleven hydrogen bonding interactions (N–H⋯O and C–H⋯O) via the formation of a Cu2+ assisted 1D coordination polymer [{CuL22224}SO4]α, (3). The coordinating property of the –CN of L2222 is reflected in 3, as it directly coordinates to the Cu2+ that assists the formation of the 1D coordination polymer. Second sphere coordination of SO42− in the assembly of L2222 is also established with Co2+ in its complex, [CoL22222(H2O)4]SO4, (4). However, in this case the metal ion prefers to form a coordination complex, as observed in 1 and 2, instead of the 1D-polymeric network in 3. The solution state UV-Vis studies of L1111 with various copper salts, such as Cu(ClO4)2, CuSO4, Cu(NO3)2, CuCl2 and their mixtures show the selective formation of 1. Cu2+ selective second sphere coordination of SO42− in solution is also demonstrated by UV-Vis studies of the complex isolated from the mixtures of various Cu2+ salts or SO42− salts of different metal ions. Furthermore, the selective formation of complex 1 is also demonstrated when complexation of CuSO4 is carried out with mixtures of L1111 and L2222 in MeOH–H2O.

Halogen-bonding-triggered supramolecular gel formation

Supramolecular gels are topical soft materials involving the reversible formation of fibrous aggregates using non-covalent interactions. There is significant interest in controlling the properties of such materials by the formation of multicomponent systems, which exhibit non-additive properties emerging from interaction of the components. The use of hydrogen bonding to assemble supramolecular gels in organic solvents is well established. In contrast, the use of halogen bonding to trigger supramolecular gel formation in a two-component gel ('co-gel') is essentially unexplored, and forms the basis for this study. Here, we show that halogen bonding between a pyridyl substituent in a bis(pyridyl urea) and 1,4-diiodotetrafluorobenzene brings about gelation, even in polar media such as aqueous methanol and aqueous dimethylsulfoxide. This demonstrates that halogen bonding is sufficiently strong to interfere with competing gel-inhibitory interactions and create a 'tipping point' in gel assembly. Using this concept, we have prepared a halogen bond donor bis(urea) gelator that forms co-gels with halogen bond acceptors.

1D coordination network formed by a cadmium based pyridyl urea helical monomer

Herein, we report the metal complexation properties of a macrocyclic ligand (L) that contains three pyridines as well as three urea groups. Linear and strand like ligands are typically used to afford helical coordination polymer. Our reported macrocyclic ligand (L) has remarkable flexibility and can twist upon dative bond formation. Two macrocyclic ligands complex with three cadmium atoms to form a helicate monomeric structure [Cd3L2(H2O)6(CH3CN)2]6+, which extends to a 1D polymeric structure via hydrogen-bonding. We also investigated the binding property of this new ligand in solution by NMR and UV–Vis spectroscopy. These results together with diffusion NMR studies suggest that in solution this ligand also forms an oligomeric complex with cadmium.

Binding of Carboxylic Acids by Fluorescent Pyridyl Ureas

Fluorescent pyrid-2-yl ureas were prepared by treating halogenated 2-aminopyridines with hexyl isocyanate, followed by Sonogashira coupling with arylacetylenes. The sensors emit light of ∼360 nm with quantum yields of 0.05-0.1 in acetonitrile solution. Addition of strong organic acids (pK(a) < 13 in CH(3)CN) shifts the fluorescence band to lower energy, and clean isoemissive behavior is observed. Fluorescence response curves (i.e., F/F(0) vs [acid](total)) are hyperbolic in shape for CCl(3)COOH and CF(3)COOH, with association constants on the order of 10(3) M(-1) for both acids. (1)H NMR titrations and DFT analyses indicate that trihaloacetic acids bind in ionized form to the receptors. Pyridine protonation disrupts an intramolecular H-bond, thereby unfolding an array of ureido NH donors for recognition of the corresponding carboxylates. Methanesulfonic acid protonates the sensors, but no evidence for conjugate base binding at the urea moiety is found by NMR. An isosteric control compound that lacks an integrated pyridine does not undergo significant fluorescence changes upon acidification.

Alkali Metal Ions As Probes of Structure and Recognition Properties of Macrocyclic Pyridyl Urea Hosts

We report the one-pot synthesis of three symmetrical macrocyclic pyridyl urea hosts. X-ray crystal studies were used to confirm the structures of the free hosts and their host.guest complexes with alkali metal ions. These solid-state studies revealed the interactions that were important for binding cations (Li(+), Na(+), and K(+)). The affinity of these hosts for alkali metal salts were evaluated in solution (CD(3)CN), and the stoichiometries of the solution complexes were compared with their solid-state structures. Two of these hosts showed high affinity for LiBF(4), which was primarily due to strong interactions between the urea oxygens and the cations with pyridine nitrogens contributing additional stabilizing interactions.

Gradual Transition from NH···Pyridyl Hydrogen Bonding to the NH···O Tape Synthon in Pyridyl Ureas

We report the synthesis and X-ray crystal structures of a series of pyridyl ureas of the type currently topical in anion binding and supramolecular gelation applications, along with their anion-binding ability in solution. The structures of the simple pyridyl ureas are dominated by urea···N(pyridyl) hydrogen bonding, because of steric congestion of the urea carbonyl by intramolecular CH···O interations. However, introducing a further competing synthon in the form of alkenic or π-stacking interactions causes a gradual changeover, through a number of interesting intermediate hydrogen bonding motifs, to the urea α-tape arrangement.

Recognition of a dicarboxylic acid with dipicolyl urea in solution and in solid phases: intramolecular hydrogen bond inhibiting both pyridine nitrogens from binding carboxyl groups

Recognition of a dicarboxylic acid in solution as well as in the solid phase by the pyridyl urea based pseudoditopic receptor 1 has been studied. The X-ray structures of both the receptor and its complex with 1,4-phenylenediacetic acid are also presented. Intramolecular hydrogen bonding inhibits both the pyridine ring nitrogens from forming hydrogen bonds with the carboxyl group and force the receptor to behave in a monotopic manner, using the syn urea amide moiety to bind carboxyl group of a dicarboxylic acid to form a 2:1 complex. Binding of receptor 1 with a monocarboxylic acid is also compared.

Hydrogen Bonding in Crystal Structures of N,N‘-Bis(3-pyridyl)urea. Why Is the N−H···O Tape Synthon Absent in Diaryl Ureas with Electron-Withdrawing Groups?

The urea tape α-network of bifurcated N−H···O hydrogen bonds is a common motif in diaryl ureas and their molecular complexes. We analyzed the X-ray crystal structures of N,N‘-bis(3-pyridyl)urea 3 and some of its derivatives: hydrates of stoichiometry 3·(4/3)H2O and 3·2H2O, cocrystals 3·SA and 3·FA·H2O with succinic acid and fumaric acid, bis pyridine N-oxide 8, and bis N-methylpyridinium iodide 9. Crystal packing in pyridyl urea structures is directed by N−H···Npyridyl, N−H···Owater, N−H···Oacid, and N−H···I- hydrogen bonds instead of the common one-dimensional N−H···Ourea tape. We postulated that the urea tape is absent in these structures because the CO acceptor is weakened by two intramolecular C−H···Ourea interactions (synthon III) in a planar molecular conformation. Electrostatic surface potential (ESP) charges (DFT-B3LYP/6-31G*) showed that the C−H···O interactions sufficiently reduce the electron density at the urea O, and so other electronegative atoms, such as pyridyl N, H2O, COOH, and I-, become viable hydrogen-bond acceptors for the strong NH donors. 1H NMR difference nOe confirmed that the planar conformation of dipyridyl urea 3 in the solid-state persists in solution. Interestingly, even though the strong hydrogen-bond motifs changed in structures of 3, the C−H···O interactions of synthon III (energy 4.6−5.0 kcal/mol) occurred throughout the family. In addition to dipyridyl urea, other electron-withdrawing diaryl ureas, e.g., those with phenylpyridyl and phenyl-nitrophenyl groups, also deviated from the prototype N−H···O tape because of the interference from weak C−H···O hydrogen bonds. Therefore, when one or both aryl rings have hydrogen-bond acceptor groups (e.g., pyridine, PhNO2), the NH donor(s) preferentially bond to pyridyl N, nitro O, or solvent O atom instead of the urea CO acceptor. We classify supramolecular organization in diaryl ureas into those with the α-network (twisted molecular conformation) or non-urea tape structures (stable, planar conformation) depending on the substituent group. Our results suggest a model to steer urea crystal structures toward the tape synthon (Ph and electron-donating groups) or with non-urea hydrogen-bond motifs and a high probability for urea···solvent hydrogen bonding (electron-withdrawing groups) by appropriate selection of functional aryl and heterocyclic groups.