Design and synthesis of 2(1H)-pyrazinones as inhibitors of protein kinases

Caldwell, John; Veillard, Nicolas; Collins, Ian

doi:10.1016/j.tet.2012.09.039

Cited by 16 publications

(12 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All reagents and solvents, including 2, were obtained from commercial suppliers and were of at least reagent grade, and used as received, unless otherwise stated. The ligands 1 and 3-6 were prepared by modified literature procedures [53][54][55][56][57][58]. Full experimental, FT-IR spectroscopic details and the single-crystal [59][60][61][62][63][64][65][66] and powder X-ray experimental [67][68][69], and structure refinements for 1•CuBr-6•CuBr (CCDC numbers: 2001484-2001491) are given in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

“…To test our hypothesis, we synthesized six chloro-substituted pyrazin-2-amine ligands (1-6) using procedures reported in the literature [53][54][55][56][57], and each ligand was combined with CuBr 2 in a 1:2 metal:ligand ratio. The CuBr complexes of these ligands were obtained by exploiting the known redox activity of Cu(II) halides in the presence of organic carbonyl compounds [31].…”

Section: -H•••n Pz (Pz = Pyrazine) Hydrogen Bonds and C-cl•••br Halogmentioning

confidence: 99%

See 1 more Smart Citation

Hydrogen and Halogen Bond Mediated Coordination Polymers of Chloro-Substituted Pyrazin-2-Amine Copper(I) Bromide Complexes

et al. 2020

View full text Add to dashboard Cite

A new class of six mono- (1; 3-Cl-, 2; 5-Cl-, 3; 6-Cl-) and di-(4; 3,6-Cl, 5; 5,6-Cl-, 6; 3,5-Cl-) chloro-substituted pyrazin-2-amine ligands (1–6) form complexes with copper (I) bromide, to give 1D and 2D coordination polymers through a combination of halogen and hydrogen bonding that were characterized by X-ray diffraction analysis. These Cu(I) complexes were prepared indirectly from the ligands and CuBr2 via an in situ redox process in moderate to high yields. Four of the pyrazine ligands, 1, 4–6 were found to favor a monodentate mode of coordination to one CuI ion. The absence of a C6-chloro substituent in ligands 1, 2 and 6 supported N1–Cu coordination over the alternative N4–Cu coordination mode evidenced for ligands 4 and 5. These monodentate systems afforded predominantly hydrogen bond (HB) networks containing a catenated (μ3-bromo)-CuI ‘staircase’ motif, with a network of ‘cooperative’ halogen bonds (XB), leading to infinite polymeric structures. Alternatively, ligands 2 and 3 preferred a μ2-N,N’ bridging mode leading to three different polymeric structures. These adopt the (μ3-bromo)-CuI ‘staircase’ motif observed in the monodentate ligands, a unique single (μ2-bromo)-CuI chain, or a discrete Cu2Br2 rhomboid (μ2-bromo)-CuI dimer. Two main HB patterns afforded by self-complimentary dimerization of the amino pyrazines described by the graph set notation R22(8) and non-cyclic intermolecular N–H∙∙∙N’ or N–H∙∙∙Br–Cu leading to infinite polymeric structures are discussed. The cooperative halogen bonding between C–Cl∙∙∙Cl–C and the C–Cl∙∙∙Br–Cu XB contacts are less than the sum of the van der Waals radii of participating atoms, with the latter ranging from 3.4178(14) to 3.582(15) Å. In all cases, the mode of coordination and pyrazine ring substituents affect the pattern of HBs and XBs in these supramolecular structures.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: -H•••n Pz (Pz = Pyrazine) Hydrogen Bonds and C-cl•••br Halogmentioning

confidence: 99%

Hydrogen and Halogen Bond Mediated Coordination Polymers of Chloro-Substituted Pyrazin-2-Amine Copper(I) Bromide Complexes

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Quinoxaline derivatives are known to act as aldose reductase (ALR 2 ) inhibitors and are active towards chronic diabetic complications including neuropathy, nephropathy, cataracts and retinopathy [ 13 – 14 ]. On the other hand, piperazinone condensed tetrahydroisoquinolines (THIQs) are widespread in nature with interesting biological activities [ 15 ]. They are also found to be building blocks for the synthesis of many alkaloids ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

Rao

Ramanathan

2017

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

An efficient and alternative synthetic approach has been developed to prepare various N-(arylethyl)piperazine-2,6-diones from 4-benzenesulfonyliminodiacetic acid and primary amines using carbonyldiimidazole in the presence of a catalytic amount of DMAP at ambient temperature. Piperazine-2,6-diones are successfully transformed to pharmaceutically useful pyridopyrazines or pyrazinoisoquinolines and ene-diamides via an imide carbonyl group activation strategy using a Brønsted acid. Subsequent dehydrosulfonylation reactions of the ene-diamides, in a one pot manner, smoothly transformed them to substituted pyrazinones. A concise synthesis of praziquantel (1) has also been achieved through this method.

show abstract

“…Recently, cis -3,4-dihydro hamacanthin B was reported to be a potent bacterial methicillin-resistant Staphylococcus protein kinase (PK) inhibitor (MRSA-PK inhibitor) with an IC 50 value of 0.016 µM and significant selectivity over human protein kinase isoforms [13]. Furthermore, the 2(1 H )-pyrazinone scaffold is present as core moiety in PK inhibitors [14]. Among human PK are validated drug targets in oncology; over-activated RTK including VEGFR, PDGFR and c-kit are considered to be major targets for the development of clinically effective inhibitors [15,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the pyrazin-2(1 H )-one core was reported to be a key binding motif to PK [14]. In contrast, neither the 3,5-bis-indole-piperazin-2-one nor the 3,5-bis-indole-3,4-dihydropyrazin-2(1 H )-one core of hamacanthins produced plausible docking poses.…”

Section: Introductionmentioning

confidence: 99%

Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors

Pinchuk

Johannes

Gul³

et al. 2013

Marine Drugs

View full text Add to dashboard Cite

In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge alkaloids) by Molecular Modeling studies as core binding motif in the ATP pocket of receptor tyrosine kinases (RTK), which are validated drug targets for the treatment of various neoplastic diseases. Structure-based design studies on a human RTK member PDGFR (platelet-derived growth factor receptor) suggested a straight forward lead optimization strategy. Accordingly, we focused on a Medicinal Chemistry project to develop pyrazin-2(1H)-ones as optimized PDGFR binders. In order to reveal Structure-Activity-Relationships (SAR), we established a flexible synthetic route via microwave mediated ring closure to asymmetric 3,5-substituted pyrazin-2(1H)-ones and produced a set of novel compounds. Herein, we identified highly potent PDGFR binders with IC50 values in an enzymatic assay below µM range, and possessing significant activity against PDGFR dependent cancer cells. Thus, marine hamacanthin-derived pyrazin-2(1H)-ones showing interesting properties as lead for their further development towards potent PDGFR-inhibitors.

show abstract

Design and synthesis of 2(1H)-pyrazinones as inhibitors of protein kinases

Cited by 16 publications

References 69 publications

Hydrogen and Halogen Bond Mediated Coordination Polymers of Chloro-Substituted Pyrazin-2-Amine Copper(I) Bromide Complexes

Hydrogen and Halogen Bond Mediated Coordination Polymers of Chloro-Substituted Pyrazin-2-Amine Copper(I) Bromide Complexes

Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors

Contact Info

Product

Resources

About