- Design, synthesis, in silico, and in vitro evaluation of 3-phenylpyrazole acetamide derivatives as antimycobacterial agents
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Mycobacterium tuberculosis (Mtb) is one of the most dangerous pathogens affecting immunocompetent and immunocompromised patients worldwide. Novel molecules, which are efficient and can reduce the duration of therapy against drug-resistant strains, are an
- Gaikwad, Nikhil B.,Nirmale, Krishna,Sahoo, Santosh K.,Ahmad, Mohammad N.,Kaul, Grace,Shukla, Manjulika,Nanduri, Srinivas,Das Gupta, Arunava,Chopra, Sidharth,Yaddanapudi, Madhavi V.
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- Selective Synthesis of Site-Differentiated Fe4S4 and Fe6S6 Clusters
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Obtaining rational control over the structure and nuclearity of metalloclusters is an ongoing challenge in synthetic Fe-S cluster chemistry. We report a new family of tridentate imidazolin-2-imine ligands L(NImR)3 that can bind [Fe4S4]2+ or [Fe6S6]3+ clusters, depending on the steric profile of the ligand and the reaction stoichiometry. A high-yielding synthetic route to L(NImR)3 ligands (where R is the imidazolyl N substituents) from trianiline and 2-chloroimidazolium precursors is described. For L(NImMe)3 (tris(1,3,5-(3-(N,N-dimethyl-4,5-diphenylimidazolin-2-imino)phenylmethyl))benzene), metalation with 1 equiv of [Ph4P]2[Fe4S4Cl4] and 3 equiv of NaBPh4 furnishes a mixture of products, but adjusting the stoichiometry to 1.5 equiv of [Ph4P]2[Fe4S4Cl4] provides (L(NImMe)3)Fe6S6Cl6 in high yield. Formation of an [Fe6S6]3+ cluster using L(NImTol)3 (tris(1,3,5-(3-(N,N-bis(4-methylphenyl)-4,5-diphenylimidazolin-2-imino)phenylmethyl))benzene) is not observed; instead, the [Fe4S4]2+ cluster [(L(NImTol)3)(Fe4S4Cl)][BPh4] is cleanly generated when 1 equiv of [Ph4P]2[Fe4S4Cl4] is employed. The selectivity for cluster nuclearity is rationalized by the orientation of the imidazolyl rings whereby long N-imidazolyl substituents preclude formation of [Fe6S6]3+ clusters but not [Fe4S4]2+ clusters. Thus, the structure and nuclearity of L(NImR)3-bound Fe-S clusters may be selectively controlled through rational modification the ligand's substituents.
- McSkimming, Alex,Suess, Daniel L.M.
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p. 14904 - 14912
(2018/11/27)
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- COMPOUND OF 5-HYDROXYL-1,7-NAPHTHYRIDINE SUBSTITUTED BY ARYL OR HETEROARYL, PREPARATION METHOD THEREOF AND PHARMACEUTICAL USE THEREOF
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Disclosed are a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, pharmaceutical compositions and uses thereof in the preparation of a medicine for inhibiting HIF prolyl hydroxylase or a medicine for promoting the generation of endogenous EPO, wherein in the formula (I), R1 and R2 are each independently hydrogen; R3 is hydrogen or C1-3 alkyl; and Ar is an aromatic ring or an heteroaromatic ring selected from a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring and a substituted benzene ring.
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Paragraph 0154
(2018/03/25)
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- Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation of Enaminones with Vinyl Esters through C-H Bond Functionalization
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An expedient [5 + 1] annulation method via Rh(III)-catalyzed C-H bond functionalization of enaminones to synthesize polyaromatic rings is described. The reaction tolerates a broad range of functional groups and offers a new entry to construct polycyclic a
- Liang, Gaohui,Rong, Jiaxin,Sun, Wangbin,Chen, Gengjia,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
(2018/11/23)
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- Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation of Enaminones with Vinyl Esters through C-H Bond Functionalization
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An expedient [5 + 1] annulation method via Rh(III)-catalyzed C-H bond functionalization of enaminones to synthesize polyaromatic rings is described. The reaction tolerates a broad range of functional groups and offers a new entry to construct polycyclic a
- Liang, Gaohui,Rong, Jiaxin,Sun, Wangbin,Chen, Gengjia,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
p. 7326 - 7331
(2018/11/25)
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- Rh(III)-Catalyzed Enaminone-Directed C-H Coupling with α-Diazo-α-phosphonoacetate for Reactivity Discovery: Fluoride-Mediated Dephosphonation for C-C Coupling Reactions
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Rh(III)-catalyzed enaminone-directed C-H coupling with α-diazo-α-phosphonoacetate has been used for the identification of fluoride-mediated dephosphonation C-C coupling reactivity for the synthesis of 4-hydroxy-1-naphthoates. Intermolecular C-C coupling of α-phosphonoacetate and benzaldehyde for (E)-selective α,β-unsaturated ester synthesis has also been achieved.
- Song, Chao,Yang, Chen,Zeng, Hua,Zhang, Wenjing,Guo, Shan,Zhu, Jin
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supporting information
p. 3819 - 3823
(2018/07/22)
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- Assessment of new triplet forming artificial nucleobases as RNA ligands directed towards HCV IRES IIId loop
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We report the synthesis of two new artificial nucleobase scaffolds, 1 and 2, featuring adequate hydrogen bonding donors and acceptors for the molecular recognition of U:A and C:G base pairs, respectively. The tethering of these structures to various amino acids and the assessment of these artificial nucleobase-amino acid conjugates as RNA ligands against a model of HCV IRES IIId domain are also reported. Compound 1e displayed the highest affinity (Kd twice lower than neomycin – control). Moreover, it appears that this interaction is enthalpically and entropically favored.
- Safir Filho, Mauro,Martin, Anthony R.,Benhida, Rachid
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supporting information
p. 1780 - 1783
(2017/04/03)
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- 4 - Phenyl - 2 - amino pyrimidine compound and its preparation method and application
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The invention discloses a 4-phenyl-2-aminopyrimidine compound, the structure of which is shown in the general formula I, wherein X is shown in the specification, R0 is hydrogen, methyl or ethyl; R1 is hydrogen, methyl, ethyl or isopropyl; R2 is isopropyl,
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Paragraph 0050-0052
(2018/03/24)
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- For detecting imaging agent of neurological disorders
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Imaging agents of formulas (I)-(V) and methods for detecting neurological disorders comprising administering to a patient in need compounds of formulas (I)-(V) capable of binding to tau proteins and β-amyloid peptides are presented herein. The invention also relates to methods of imaging Aβ and tau aggregates comprising introducing a detectable quantity of pharmaceutical formulation comprising a radiolabeled compound of formulas (I)-(V) and detecting the labeled compound associated with amyloid deposits and/or tau proteins in a patient. These methods and compositions enable preclinical diagnosis and monitoring progression of AD and other neurological disorders.
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Paragraph 1027-1029
(2016/10/08)
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- Protective effect of novel substituted nicotine hydrazide analogues against hypoxic brain injury in neonatal rats via inhibition of caspase
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In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50 = 19.4 ± 2.5 μM). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury.
- Deng, Chang-Bo,Li, Juan,Li, Lu-Yi,Sun, Feng-Jie
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supporting information
p. 3195 - 3201
(2016/06/13)
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- 3,4-DIARYLPYRAZOLES AS PROTEIN KINASE INHIBITORS
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3,4-diarylpyrazole derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
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Page/Page column 129
(2010/04/03)
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- Identification of pyrazolo[1,5-a]pyrimidine-3-carboxylates as B-Raf kinase inhibitors
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B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and inhibitors of B-Raf could be used in the treatment of melanomas, colorectal cancer, and other Ras related human cancers. We have identified novel small molecule pyrazolo[1,5-a]pyr
- Gopalsamy, Ariamala,Ciszewski, Greg,Hu, Yongbo,Lee, Frederick,Feldberg, Larry,Frommer, Eileen,Kim, Steven,Collins, Karen,Wojciechowicz, Donald,Mallon, Robert
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scheme or table
p. 2735 - 2738
(2009/12/31)
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- Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors
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Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This s
- Gopalsamy, Ariamala,Ciszewski, Greg,Shi, Mengxiao,Berger, Dan,Hu, Yongbo,Lee, Frederick,Feldberg, Larry,Frommer, Eileen,Kim, Steven,Collins, Karen,Wojciechowicz, Donald,Mallon, Robert
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scheme or table
p. 6890 - 6892
(2010/05/19)
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- 3-AZABICYCLO [3.1.0] HEXANE DERIVATIVES AS VANILLOID RECEPTOR LIGANDS
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The present invention relates to 3-azabicyclo[3.1.0]hexane derivatives, which are useful as vanilloid receptor (VR) ligands, methods of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.
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Page/Page column 38-39
(2009/08/16)
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- Synthesis of deuterium-labeled zaleplon-d5 as an internal standard
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Zaleplon is licensed for the short-term treatment of insomnia. Excessive usage causes side effects; hence, the drug is controlled. Identifying zaleplon in a drug abuser requires an isotope-labeled internal standard. This work presents a synthesis of stable isotope-labeled internal standard for zaleplon, zaleplon-d5, by a five-step synthetic sequence. Copyright
- Shaikh, Ajam C.,Chen, Chinpiao
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- Dihydropyrazolo[1,5-A]pyrimidine and dihydroimidazo[1,5-A]pyrimidine derivatives and methods of use thereof
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The present invention relates to dihydropyrazolo[1,5-a]pyrimidine and dihydroimidazo[1,5-a]pyrimidine derivatives, compositions comprising an effective amount of a dihydropyrazolo[1,5-a]pyrimidine or a dihydroimidazo[1,5-a]pyrimidine derivative and method
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Page/Page column 11
(2008/06/13)
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- Pyrazolo[1,5-A]pyrimidine derivatives and methods of use thereof
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The present invention relates to pyrazolo[1,5-a]pyrimidine derivatives, compositions comprising an effective amount of a pyrazolo[1,5-a]pyrimidine derivative and methods for treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pyrazolo[1,5-a]pyrimidine derivative.
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Page/Page column 22
(2010/11/28)
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- Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel antiproliferative agents: Exploration of core and headpiece structure-activity relationships
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A novel series of antiproliferative agents containing pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides, selective for p21-deficient cells, were identified by high-throughput screening. Exploration of the SAR relationships in the headpiece, core, and tailpiece
- Powell, Dennis,Gopalsamy, Ariamala,Wang, Yanong D.,Zhang, Nan,Miranda, Miriam,McGinnis, John P.,Rabindran, Sridhar K.
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p. 1641 - 1645
(2007/10/03)
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- Method of using substituted pyrazolo [1,5-a] pyrimidines
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This invention relates to novel methods of use of certain pyrazolo[1,5-a]pyrimidine compounds and the therapeutically acceptable salts thereof. This invention also relates to novel methods of using these compounds as anti-proliferative agents in mammals, including humans.
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Page/Page column 43
(2010/10/20)
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- Substituted pyrazolo[1,5-a] pyrimidines and process for making same
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This invention relates to novel pyrazolo[1,5-a]pyrimidine compounds and the therapeutically acceptable salts thereof. These compounds are useful as anti-proliferative agents in mammals, including humans.
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Page/Page column 48-49
(2010/10/20)
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- Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: Parallel synthesis for lead optimization of amide region
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A novel series of p21 chemoselective agents containing a pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides were identified by high throughput screening. Optimization of the amide region by parallel synthesis and the iterative design toward understanding structu
- Gopalsamy, Ariamala,Yang, Hui,Ellingboe, John W.,Tsou, Hwei-Ru,Zhang, Nan,Honores, Erick,Powell, Dennis,Miranda, Miriam,McGinnis, John P.,Rabindran, Sridhar K.
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p. 1591 - 1594
(2007/10/03)
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- N-phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: Structure-activity studies and demonstration of in vivo activity
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Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3- (aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2- furanylamidine (77) (K(i-nNOS) = 0.006 μM; K(i-eNOS) = 0.35 μM; K(i-iNOS) = 0.16 μM). Finally, α-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (K(i- nNOS) = 0.011 μM; K(i-eNOS) = 1.1 μM; K(i-iNOS) = 0.48 μM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.
- Collins, Jon L.,Shearer, Barry G.,Oplinger, Jeffrey A.,Lee, Shuliang,Garvey, Edward P.,Salter, Mark,Duffy, Claire,Burnette, Thimysta C.,Furfine, Eric S.
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p. 2858 - 2871
(2007/10/03)
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