- Synthesis of novel pyridine and pyrimidine derivatives as potential inhibitors of HIV-1 reverse transcriptase using palladium-catalysed C-N cross-coupling and nucleophilic aromatic substitution reactions
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Palladium-mediated cross-coupling reactions are used in the successful construction of a small library of flexible heteroatom-linked diarylpyridine target compounds, including pyridines bearing a secondary amide substituent. Heteroatom-linked diarylpyrimidine derivatives bearing a chlorine substituent are prepared by base-catalysed nucleophilic aromatic substitution reactions without the need for palladium catalysis.
- Changunda, Charles R.K.,Rousseau, Amanda L.,Basson, Adriaan E.,Bode, Moira L.
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p. 152 - 170
(2021/05/27)
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- Hemozoin inhibiting 2-phenylbenzimidazoles active against malaria parasites
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The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1H-benzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124. Further narrowing to compounds with terminal aryl ring substituents only, reduced the library to 18, 83% of which were found to inhibit β-hematin formation 100 μM and 50% parasite growth 2 μM. Four compounds showed nanomolar parasite growth inhibition activities, no cross-resistance in a chloroquine resistant strain and low cytotoxicity. QSAR analysis showed a strong association of parasite growth inhibition with inhibition of β-hematin formation and the most active compound inhibited hemozoin formation in P. falciparum, with consequent increasing exchangeable heme. Pioneering use of molecular docking for this system demonstrated predictive ability and could rationalize observed structure activity trends.
- L'abbate, Fabrizio P.,Müller, Ronel,Openshaw, Roxanne,Combrinck, Jill M.,de Villiers, Katherine A.,Hunter, Roger,Egan, Timothy J.
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p. 243 - 254
(2018/10/15)
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- Nitrogenous heterocyclic compound with nematocidal activity, preparation method and application thereof
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The invention relates to a nitrogenous heterocyclic compound with nematocidal activity, a preparation method and application thereof. Specifically, the invention discloses a compound with a formula (I) or an optical isomer, cis-trans isomer or acceptable salt in agricultural pharmacology and a preparation method thereof. The invention further discloses an agricultural composition containing the compound and application thereof. The compound has excellent nematocidal activity.
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Paragraph 0155; 0156; 0157
(2018/07/30)
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- Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure-Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal Structure Analysis with Human CathepsinL
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The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 substituent led to high-affinity ligands with inhibition constants down to 2nM for compounds bearing cyclohexyl substituents. Systematic investigations on the S3 pocket revealed its potential to achieve high activities with aromatic vectors that undergo stacking interactions with the planar peptide backbone forming part of the pocket. X-ray crystal structure analysis with the structurally related enzyme human cathepsinL confirmed the binding mode of the triazine ligand series as proposed by molecular modeling. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved for ligands decorated with the best substituents identified through the optimization cycles. In cell-based assays, the introduction of a basic side chain on the inhibitors resulted in a 35-fold increase in antitrypanosomal activity. Finally, bioisosteric imidazopyridine nitriles were studied in order to prevent off-target effects with unselective nucleophiles by decreasing the inherent electrophilicity of the triazine nitrile headgroup. Using this ligand, the stabilization by intramolecular hydrogen bonding of the thioimidate intermediate, formed upon attack of the catalytic cysteine residue, compensates for the lower reactivity of the headgroup. The imidazopyridine nitrile ligand showed excellent stability toward the thiol nucleophile glutathione in a quantitative invitro assay and fourfold lower cytotoxicity than the parent triazine nitrile.
- Ehmke, Veronika,Winkler, Edwin,Banner, David W.,Haap, Wolfgang,Schweizer, W. Bernd,Rottmann, Matthias,Kaiser, Marcel,Freymond, Celine,Schirmeister, Tanja,Diederich, Francois
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supporting information
p. 967 - 975
(2013/07/27)
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- Titanocene(III)-catalyzed conversion of N-(epoxyalkyl)anilines into indolines
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Densely substituted indolines and azaindolines can be obtained by the titanocene(III) chloride catalyzed reductive opening of N-(oxiran-2-ylmethyl) anilines. The reaction optimization, substrate scope, and limitations are discussed, and a mechanistic pathway for the epoxideopening rearrangement is proposed. ARKAT-USA, Inc.
- MacIejewski, John P.,Wipf, Peter
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experimental part
p. 92 - 119
(2011/06/20)
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- Catalytic syntheses of N-heterocyclic ynones and ynediones by in situ activation of carboxylic acids with oxalyl chloride
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Breaking the bottleneck: α-Keto carboxylic acids and N-heterocyclic carboxylic acids are activated in situ with oxalyl chloride then catalytically alkynylated to give ynediones and N-heterocyclic ynones efficiently in a one-pot fashion. 5-Acylpyrazoles and 2-phenylaminopyrimidines, potentially interesting for pharmaceutical applications, are readily synthesized in concise one-pot, three-component syntheses. Copyright
- Boersch, Christina,Merkul, Eugen,Mueller, Thomas J. J.
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supporting information; experimental part
p. 10448 - 10452
(2011/12/05)
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- Titanocene(III)-catalyzed formation of indolines and azaindolines
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(Chemical Equation Presented) Reductive cyclization of epoxides tethered to substituted anilines and aminopyridines in the presence of 3 mol % of titanocene dichloride and stoichiometric manganese metal promotes a radical annulation to form 3,3-disubstituted indolines and azaindolines.
- Wipf, Peter,Maciejewski, John P.
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supporting information; experimental part
p. 4383 - 4386
(2009/05/30)
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- TETRAHYDROISOQUINOLINE-AND TETRAHYDROBENZAZEPINE DERIVATIVES AS IGF-1R INHIBITORS
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Compounds of the formula (I): where R2, R5, R6 have the meanings as given in the description, and U, V and W, respectively, may be CR2', CR4' and CR6', respectively (with the definitions of R2', R4' and R6' again as in the description), or may be N, were io synthesized. They were found to down-regulate or inhibit the expression or function of the IGF-1 receptor.
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Page/Page column 36
(2008/06/13)
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- Polymer supported palladium N-heterocyclic carbene complexes: Long lived recyclable catalysts for cross coupling reactions
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Polymer supported palladium complexes, containing a pyridyl bis N-heterocyclic carbene ligand system derived from isonicotinic acid, provide highly stable catalysts for Heck and Suzuki cross coupling reactions. These heterogenous catalysts can be recycled ≥14 times with no loss of activity.
- Steel, Patrick G.,Teasdale, Christopher W.T.
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p. 8977 - 8980
(2007/10/03)
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- Exploiting the versatile assembly of arylpyridine fluorophores for wavelength tuning and SAR
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(Matrix presented) The facile modular assembly of polyarylpyridine fluorophores provides two important advantages in the development of fluorescent chemosensors: it allows rapid dissection of the structural requirements for fluorescent chemosensing and it allows dramatic tuning of emission wavelength by changes in a substituent remote from the binding site.
- Fang, Albert G.,Mello, Jesse V.,Finney, Nathaniel S.
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p. 967 - 970
(2007/10/03)
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- Convenient synthesis and transformation of 2,6-dichloro-4-iodopyridine
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(Matrix Presented) We describe a convenient scalable synthesis of 2,6-dichloro-4-iodopyridine and demonstrate its utility by stepwise elaboration to a number of 2,4,6-trisubstituted pyridines.
- Mello, Jesse V.,Finney, Nathaniel S.
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p. 4263 - 4265
(2007/10/03)
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