Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo4,5-cpyridin-2-ones and imidazo4,5-cpyridines were designed based on combination ...principles by merging the structures of β-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo4,5-cpyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.
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•A novel class of diaryl-substituted fused heterocycles were designed and synthesized.•Compound 20b was identified as the first bifunctional agent that can target both tubulin and katanin.•The in vivo assays verified that 20b inhibited xenograft tumor growth with good pharmacokinetic characteristics.
•Pyridin-2-one in cocrystals, as a ligand in complexes or protonated in an ionic liquid.•Homoleptic complex of pyridin-2-one (Hhp) with vanadium(III).•High thermal stability of ZnCl2(Hhp)2.
Reactions ...of anhydrous chlorides VCl3 or ZnCl2 and pyridin-2-one (C5H5NO = Hhp) afforded novel homoleptic ionic V(Hhp)6Cl3.CH2Cl2 (1) or molecular ZnCl2(Hhp)2 (2) complexes. Reaction of MnCl2.2H2O and Hhp in tetrahydrofuran (THF) gave cocrystals of MnCl2(H2O)2n.2nHhp (3). After addition of chlorotrimethylsilane to remove water in a mixture of MnCl2.2H2O and Hhp in THF, protonation of Hhp was observed and H2hpCl (4) was isolated. Single crystal X-ray analysis revealed a monodentate coordination of carbonyl oxygen in complexes 1 and 2.
The results of thermal analysis of crystals 1, 2 and 4 show their thermal stability. The decomposition of complex 1 starts at 60°C, while complex 2 melts at 175°C and decomposes only at 185°C. Compound 4 can be classified as an ionic liquid due to its low melting point (86°C). The release of ligated Hhp in 1 and 2 occurs up to 450°C, while 99.4% mass loss in 4 is observed at the lower temperature of 220°C.
The difference in thermal stability is explained by the ligation of Hhp, hydrogen bonds and other weak interactions. Hydrogen bonds and an off-center parallel stacking arrangement of the coordinated Hhp form a 3D structure in 2 and layers in 1. The H2hp+ and chloride ions in 4 are connected by hydrogen bonds and form only chains without other weak interactions.
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A general and simple synthesis of 2,4,6-trisubstituted pyridines and fused pyridine-2-ones from bromoacetic acid is developed via a DMAP-promoted in situ activation strategy. In this protocol, ...readily accessible bromoacetic acid has been effectively employed as a 2C synthon to undergo formal 2+4 cycloadditions with diverse acyclic and cyclic 1-azadienes. Low costs of the reagents and materials, mild reaction conditions and broad functional-group tolerance make this protocol applicable for practical and scalable synthesis.
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We identified novel potent inhibitors of p38 mitogen‐activated protein (MAP) kinase using a structure‐based design strategy, beginning with lead compound, ...3‐(butan‐2‐yl)‐6‐(2,4‐difluoroanilino)‐1,3‐dihydro‐2H‐imidazo4,5‐bpyridin‐2‐one (1). To enhance the inhibitory activity of 1 against production of tumor necrosis factor‐α (TNF‐α) in human whole blood (hWB) cell assays, we designed and synthesized hybrid compounds in which the imidazo4,5‐bpyridin‐2‐one core was successfully linked with the p‐methylbenzamide fragment. Among the compounds evaluated, 3‐(3‐tert‐butyl‐2‐oxo‐2,3‐dihydro‐1H‐imidazo4,5‐bpyridin‐6‐yl)‐4‐methyl‐N‐(1‐methyl‐1H‐pyrazol‐3‐yl)benzamide (25) exhibited potent p38 inhibition, superior suppression of TNF‐α production in hWB cells, and also significant in vivo efficacy in a rat model of collagen‐induced arthritis (CIA). In this paper, we report the discovery of potent, selective, and orally bioavailable imidazo4,5‐bpyridin‐2‐one‐based p38 MAP kinase inhibitors.
Scaffold hopping: Structure‐based design with X‐ray crystallographic analysis of the complex between lead compound 1 and p38 MAP kinase, and expanding an approach for direct hydrogen bond formation with the back pocket residues of the kinase, led to potent p38 MAP kinase inhibitor 25, which was found to exhibit strong suppression of TNF‐α production in human whole blood and to have excellent in vivo efficacy in a rat CIA model.
Reactions of NiCl
·6H
O and pyridin-2-one (C
H
NO = Hhp) afforded novel molecular complexes, i.e., mononuclear NiCl
(Hhp)
(
), dinuclear NiCl
(Hhp)(H
O)
2Hhp (
) and Ni
Cl
(Hhp)
·2MeCN (
), and an ...ionic complex Ni(Hhp)
Cl
(
). Single-crystal X-ray analyses revealed two modes of Hhp ligation in these complexes: a monodentate coordination of carbonyl oxygen in all of them and an additional
-oxygen bridging coordination in the dinuclear complex
. Three bridging molecules of Hhp span two nickel(II) ions in
with a 2.9802 (
) Å separation of the metal ions. Complex
is a chlorido-bridged nickel dimer with a planar Ni
(
-Cl)
framework. Hydrogen bonds and parallel stacking arrangements of the Hhp molecules govern the connectivity patterns in the crystals, resulting in 1D structures in
and
or 2D in
. A single manganese compound MnCl
(Hhp)
(
), isostructural to
, was isolated under the similar conditions. This is in contrast to four nickel(II) chloride complexes with Hhp. Thermal analyses proved the stability of complexes
and
in argon up to 145 °C and 100 °C, respectively. The decomposition of
and
yielded nickel in argon and nickel(II) oxide in air at 800 °C.
Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have ...attracted much attention. Herein, a new series of imidazo4,5-cpyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A cyanoacetohydrazide derivative underwent a series of reactions with different nucleophilic reagents, such as hydrazine hydrate, p-chlorobenzaldehyde and salicylaldehyde, to give the condensation ...products. In addition, an arylidene malononitrile was reacted with different nitrogen nucleophiles, such as hydrazine hydrate, thiocarbohydrazide and cyanoacetohydrazide, to afford the hydrazine, hydrazone and pyridin-2-one derivatives, respectively. Furthermore, a pyridin-2-one derivative was reacted with different carbon electrophiles, such as carbon disulfide, p-chlorobenzaldehyde and acetic anhydride. The antimicrobial activities of some of the compounds were examined.
An efficient approach for the synthesis of highly substituted pyridin-2-one derivatives and α-alkylated nitriles through enzymatic multicomponent reaction (MCR) was developed. This MCR involved ...bio-mimetic reduction between 3,4-dihydropyridin-2-one and activated olefin, both of which were in situ generated in the Acylase Amano (AA)-catalyzed domino reaction starting from benzaldehyde, cyanoacetamide and ketone. A wide range of substituted benzaldehydes and ketones were accepted by this reaction. Both final products (pyridin-2-one derivatives and α-alkylated nitriles) were important skeletons and synthetic intermediates. The synthetic application of prepared α-alkylated nitrile was demonstrated by converting it into the corresponding α-alkyl-β2-amino acid with high yield.
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Multisubstituted 2-aminothiophenes 1a–c can be readily cyanoacylated via reaction with cyanoacetic acid in presence of acetic anhydride under a microwave irradiation to form the corresponding ...cyanoacetamides 2a–c, which condensed with DMF-DMA to form the corresponding enamines 4 that reacted with hydrazine hydrate to yield the aminopyrazoles 5. Moreover the cyanoacetamides 2a–c reacted with a variety of arylidenmalononitrile to afford a novel pyrido1,2-athieno3,2-epyrimidine derivatives 12a–o. In addition the enamines 4a,b reacted with malononitrile to afford the pyrido1,2-athieno3,2-epyrimidine derivatives 19a,b. The cyanoacetamides 2a,b reacted also with salicylaldehyde to afford the quinoline derivatives 24a,b. Moreover the cyanoacetamides 2a,b reacted with the enaminones 25a–c to form the corresponding Pyridin-2-one derivatives 29a–c. Reactions of 2a,c with bezenediazonium chloride afford the arylhydrazones 30a,b that reacted with chloroacetonitrile to form the acyclic product 31 which could not be further cyclized to the corresponding 4-aminopyrazole. The X-ray crystallographic analyses of seven products could be obtained thus establishing with certainty the proposed structures in this work. Most of the synthesized compounds in this investigation were tested and evaluated as antimicrobial agents.
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► The 2-aminothiophenes readily cyanoacylated under a microwave irradiation. ► A new series of pyrido1,2-athieno3,2-epyrimidine derivatives were synthesized. ► compounds 1a and 24a,b showed a patent biological activity. ► The antimicrobial activity of all the new compounds have been screened.
The title compounds C
17
H
14
BrNO
2
, (I), and C
17
H
15
NO
3
, (II), were obtained from the reaction of 6-methoxy-3,4-dihydro-2
H
-naphthalen-1-one and 2-bromonicotinaldehyde in ethanol. Compound ...(I) was the expected product and compound (II) was the oxidation product from air exposure. In the crystal structure of compound (I), there are no short contacts or hydrogen bonds. The structure does display π–π interactions between adjacent benzene rings and adjacent pyridyl rings. Compound (II) contains two independent molecules,
A
and
B
, in the asymmetric unit; both are non-planar, the dihedral angles between the methoxybenzene and 1
H
-pyridin-2-one mean planes being 35.07 (9)° in
A
and 35.28 (9)°in
B
. In each molecule, the 1
H
-pyridin-2-one unit participates in intermolecular N—H...O hydrogen bonding to another molecule of the same type (
A
to
A
or
B
to
B
). The structure also displays π–π interactions between the pyridyl and the benzene rings of non-equivalent molecules (
viz
.,
A
to
B
and
B
to
A
).
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