Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor

Ando, Makoto; Sato, Nagaaki; Nagase, Tsuyoshi; Nagai, Keita; Ishikawa, Shiho; Takahashi, Hirobumi; Ohtake, Norikazu; Itô, Junko; Hirayama, Mioko; Mitobe, Yuko; Iwaasa, Hisashi; Gomori, Akira; Matsushita, Hiroko; Tadano, Kiyoshi; Fujino, Nobukatsu; Tanaka, Sachiko; Ohe, Tomoyuki; Ishihara, Akane; Kanatani, Akio; Fukami, Tatsuki

doi:10.1016/j.bmc.2009.05.069

Cited by 19 publications

(16 citation statements)

References 28 publications

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“…The N-oxidation reaction was carried out using urea-hydrogen peroxide addition complex in trifluoro acetic acid anhydride. [16] The 6-chloro N-oxide 8 was converted into 6-oxo compound 9 using TFAA keeping the carboxylic acid ester intact. The product was then benzylated with benzyl bromide in the presence of potassium carbonate.…”

Section: Resultsmentioning

confidence: 99%

Discovery of 1‐Hydroxypyridine‐2(1H)‐thione‐6‐carboxylic Acid as a First‐in‐Class Low‐Cytotoxic Nanomolar Metallo β‐Lactamase Inhibitor

et al. 2017

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VIM2 is a carbapenem-hydrolyzing metallo β–lactamase (MBL) found in clinical isolates of ESKAPE pathogens. For drug development, currently, there is a lack of lead compounds with optimal therapeutic potential. Here we report the discovery of 1-hydroxypyridine-2(1H)-thiones-6-carboxylic acid (3) as a potent VIM2 inhibitor with a Ki of 13 nM and low cytotoxicity CC50 of 97.4 μM. We further showed this inhibitor can restore the antibiotic activity of amoxicillin against VIM-2 producing E. coli in whole cells assays. Its potential mode of binding was examined by molecular modeling and its stability in mouse and human plasma studies was assessed. Overall, 3 exhibits a remarkable 0.99 ligand efficiency against VIM2, a 6,900 fold difference in cytotoxicity from its parent compound and a therapeutic index (TI) of 880, making it a promising lead candidate for combination antibacterial therapy development.

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Section: Resultsmentioning

confidence: 99%

Discovery of 1‐Hydroxypyridine‐2(1H)‐thione‐6‐carboxylic Acid as a First‐in‐Class Low‐Cytotoxic Nanomolar Metallo β‐Lactamase Inhibitor

et al. 2017

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“…The latter was converted to 2‐chloro‐5‐methoxypyridine ( 3 ) with iodomethane in the presence of K 2 CO 3 . Using the urea · H 2 O 2 adduct and trifluoroacetic anhydride, conversion to 2‐chloro‐5‐methoxypyridine N ‐oxide ( 4 ) occurred 15. Subsequent reaction in nitrating acid gave 2‐chloro‐4‐nitro‐5‐methoxypyridine ( 5 ), that is, nitration and loss of the N ‐oxide occurred in the same reaction step.…”

Section: Resultsmentioning

confidence: 99%

“…2‐Chloro‐5‐methoxypyridine N ‐Oxide (4): The following procedure was adapted from a previously published protocol 15. Urea · H 2 O 2 adduct (2 equiv.)…”

Section: Methodsmentioning

confidence: 99%

Photoredox Properties of Homoleptic d⁶ Metal Complexes with the Electron‐Rich 4,4′,5,5′‐Tetramethoxy‐2,2′‐bipyridine Ligand

et al. 2015

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A synthetic procedure leading to 4,4Ј,5,5Ј-tetramethoxy-2,2Јbipyridine [(MeO) 4 bpy] was developed, and the first three metal complexes with this ligand were synthesized. A few ligand precursor compounds, the final ligand, and its homoleptic iron(II) complex were characterized structurally by Xray diffraction. The combination of cyclic voltammetry, optical absorption, luminescence, and transient absorption spectroscopy provided detailed insight into the electronic structure of the entire series of homoleptic Fe II , Ru II , and Os II complexes. The ruthenium(II) complex is a more potent photoreductant than the [Ru(bpy) 3 ] 2+ parent compound by [a] www.eurjic.org FULL PAPER the complexes were explored in detail, and we find that [Ru{(MeO) 4 bpy} 3 ] 2+ is indeed a very potent excited-state electron donor. The redox and photophysical properties of the new complexes are rationalized by comparison with existing data of related bpy-based complexes.

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“…This 1,2-diamine intermediate was synthesized by the addition of 5-bromo-2-fluoropyridine to an N-sulfinylketimine (Scheme 76). 103…”

Section: Scheme 73 Synthesis Of a Manzacidin C Intermediatementioning

confidence: 99%

1,2-Additions on Chiral N-Sulfinylketimines: An Easy Access to Chiral α-Tertiary Amines

Carret¹,

Poisson²,

Berthiol³

et al. 2022

Synthesis

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Chiral α-tertiary amines, a motif present in α,α-disubstituted α-amino acids, in a wide range of natural products, and many drugs and drug candidates, are important targets in organic chemistry. Among the possible strategies, 1,2-addition to chiral N-sulfinylketimines is one of the best routes to form chiral α-tertiary amines with a high level of stereoselectivity. In this review, we focus first on the addition of organometallic reagents or other nucleophiles as enols or ylides to chiral N-sulfinylketimines. Then secondly we cover a selection of applications of these additions in the synthesis of valuable biologically active compounds.1 Introduction2 1,2-Addition Reaction Methodologies2.1 Organolithium Reagent Additions2.2 Grignard Additions2.3 Organozinc Reagent Additions2.4 Organoindium Reagent Additions2.5 Organoboron Reagent Additions2.6 Strecker Reactions2.7 Palladium-Catalyzed Reactions2.8 Enols, Enolates, and Other Deprotonated Reagent Additions2.9 Ylide Additions2.10 Heteroatom Nucleophiles2.11 Miscellaneous Reactions3 Applications to the Synthesis of Biologically Active Molecules4 Conclusions

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Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor

Cited by 19 publications

References 28 publications

Discovery of 1‐Hydroxypyridine‐2(1H)‐thione‐6‐carboxylic Acid as a First‐in‐Class Low‐Cytotoxic Nanomolar Metallo β‐Lactamase Inhibitor

Discovery of 1‐Hydroxypyridine‐2(1H)‐thione‐6‐carboxylic Acid as a First‐in‐Class Low‐Cytotoxic Nanomolar Metallo β‐Lactamase Inhibitor

Photoredox Properties of Homoleptic d⁶ Metal Complexes with the Electron‐Rich 4,4′,5,5′‐Tetramethoxy‐2,2′‐bipyridine Ligand

1,2-Additions on Chiral N-Sulfinylketimines: An Easy Access to Chiral α-Tertiary Amines

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Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor

Cited by 19 publications

References 28 publications

Discovery of 1‐Hydroxypyridine‐2(1H)‐thione‐6‐carboxylic Acid as a First‐in‐Class Low‐Cytotoxic Nanomolar Metallo β‐Lactamase Inhibitor

Discovery of 1‐Hydroxypyridine‐2(1H)‐thione‐6‐carboxylic Acid as a First‐in‐Class Low‐Cytotoxic Nanomolar Metallo β‐Lactamase Inhibitor

Photoredox Properties of Homoleptic d6 Metal Complexes with the Electron‐Rich 4,4′,5,5′‐Tetramethoxy‐2,2′‐bipyridine Ligand

1,2-Additions on Chiral N-Sulfinylketimines: An Easy Access to Chiral α-Tertiary Amines

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Product

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Photoredox Properties of Homoleptic d⁶ Metal Complexes with the Electron‐Rich 4,4′,5,5′‐Tetramethoxy‐2,2′‐bipyridine Ligand