- Regioselective Hydroalkylation of Vinylarenes by Cooperative Cu and Ni Catalysis
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Disclosed here is a dual copper and nickel catalytic system with a silyl hydride source for promoting the linear selective hydroalkylation of vinylarenes. This carbon–carbon bond-forming protocol is applied to couple a variety of functionalized vinylarenes with alkyl halides applying a nickel(II) NNN pincer complex in the presence of an NHC-ligated copper catalyst. This combination allows for a 1 mol % loading of the nickel catalyst leading to turnover numbers of up to 72. Over 40 examples are presented, including applications for pharmaceutical diversification. Labeling experiments demonstrated the regioselectivity of the reaction and revealed that the copper catalyst plays a crucial role in enhancing the rate for formation of the reactive linear alkyl nickel complex. Overall, the presented work provides a complimentary approach for hydroalkylation reactions, whilst providing a preliminary mechanistic understanding of the cooperativity between the copper and nickel complexes.
- Ravn, Anne K.,Johansen, Martin B.,Skrydstrup, Troels
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supporting information
(2021/12/14)
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- Pyrimidine-2,4-diamines as antiplasmodial antifolates
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Two series of substituted pyrimidine-2,4-diamines with a flexible side chain at either the 5- or 6-position of the pyrimdine ring were designed as potential inhibitors of P. falciparum dihydrofolate reductase (DHFR). The compounds were synthesised and eva
- Seanego, Tswene D.,Klein, Hanna F.,Jansen van Vuuren, Natasha C.,Van Zyl, Robyn L.,Rousseau, Amanda L.
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p. 344 - 361
(2020/10/30)
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- Nickel-Catalyzed Multicomponent Coupling Reaction of Alkyl Halides, Isocyanides and H2O: An Expedient Way to Access Alkyl Amides
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We herein describe a Ni-catalyzed multicomponent coupling reaction of alkyl halides, isocyanides, and H2O to access alkyl amides. Bench-stable NiCl2(dppp) is competent to initiate this transformation under mild reaction conditions, thus allowing easy operation and adding practical value. Substrate scope studies revealed a broad functional group tolerance and generality of primary and secondary alkyl halides in this protocol. A plausible catalytic cycle via a SET process is proposed based on preliminary experiments and previous literature.
- Li, Qiao,Jin, Hongwei,Liu, Yunkui,Zhou, Bingwei
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supporting information
p. 3466 - 3472
(2020/09/15)
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- Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18
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GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date. Analogs were synthesized that exhibit broad modifications of the heterocyclic core and/or variation of substituents at the benzylidene moiety. The compounds were investigated in β-arrestin recruitment assays as inhibitors of human GPR18 activation by tetrahydrocannabinol (THC). Selectivity was assessed versus the cannabinoid receptors (CB1 and CB2) and versus GPR55, another orphan GPCR that interacts with cannabinoids. Phenyloxyalkyloxy-substituted benzylidenethiazinones with long alkyl chains (optimal length: hexamethylene) efficiently blocked GPR18 with similarly high potency as lead structure 5. (Z)-2-(3-(6-(4-Chlorophenoxy)hexyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB-27, 23) exhibited the best profile: it displayed an IC50 value of 650 nM at GPR18 and showed improved selectivity versus CB receptors as compared to lead structure 5. Importantly, in contrast to 5, which showed only partial inhibition (60%), 23 led to a complete blockade of THC-induced GPR18 activation and is thus a superior tool for target validation. In addition, several compounds, e.g. 18 and 22, were identified as dual GPR18/GPR55 antagonists with similar potency at both targets, and selectivity versus CB receptors.
- Schoeder, Clara T.,Kaleta, Maria,Mahardhika, Andhika B.,Olejarz-Maciej, Agnieszka,?a?ewska, Dorota,Kie?-Kononowicz, Katarzyna,Müller, Christa E.
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p. 381 - 397
(2018/06/14)
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- Nickel-Catalyzed Reductive Amidation of Unactivated Alkyl Bromides
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A user-friendly, nickel-catalyzed reductive amidation of unactivated primary, secondary, and tertiary alkyl bromides with isocyanates is described. This catalytic strategy offers an efficient synthesis of a wide range of aliphatic amides under mild conditions and with an excellent chemoselectivity profile while avoiding the use of stoichiometric and sensitive organometallic reagents.
- Serrano, Eloisa,Martin, Ruben
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supporting information
p. 11207 - 11211
(2016/10/13)
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- Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
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Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in?vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2?h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in?vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
- Chambers, Janice E.,Chambers, Howard W.,Funck, Kristen E.,Meek, Edward C.,Pringle, Ronald B.,Ross, Matthew K.
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p. 154 - 159
(2016/12/06)
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- Synthesis and biological evaluation of vinyl ether-containing azole derivatives as inhibitors of Trichophyton rubrum
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In an attempt to search for many target compounds with excellent activities, a series of vinyl ether-containing azole derivatives were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against Trichophyton rubrum in vitro indicated that most of the synthesized compounds showed excellent activities. In comparison with fluconazole, itraconazole, voriconazole, omoconazole and amphotericin B, several compounds (such as 7d, 7g and 7h) exhibited more potent inhibitory activities, suggesting that they were promising leads for the development of novel antifungal agents.
- Wang, Lulu,Yang, Wenge,Wang, Kai,Zhu, Jing,Shen, Fei,Hu, Yonghong
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scheme or table
p. 4887 - 4890
(2012/08/07)
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- Expeditious synthesis and biological evaluation of novel 2,N 6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials
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A small set of novel 2,N6-disubstituted 1,2-dihydro-1,3,5- triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal ary
- Gravestock, David,Rousseau, Amanda L.,Lourens, Anna C.U.,Moleele, Simon S.,Van Zyl, Robyn L.,Steenkamp, Paul A.
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experimental part
p. 2022 - 2030
(2011/06/21)
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- Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase
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A series of novel berberine derivatives were designed, synthesized, and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among these derivatives, compound 48a, berberine linked with 3-methylpyridi
- Huang, Ling,Luo, Zonghua,He, Feng,Lu, Jing,Li, Xingshu
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experimental part
p. 4475 - 4484
(2010/08/22)
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- Synthesis and insecticidal activity of novel carbamate derivatives as potential dual-binding site acetylcholinesterase inhibitors
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In biological systems, bivalent ligands often possess increased functional affinity for their receptors compared with monovalent ligands. On the basis of the structure of acetylcholinesterase (AChE), a series of novel carbamate heterodimetic derivatives w
- Ma, Hong-Ju,Xie, Ru-Liang,Zhao, Qian-Fei,Mei, Xiang-Dong,Ning, Jun
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experimental part
p. 12817 - 12821
(2011/10/09)
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- Discovery of highly potent novel antifungal azoles by structure-based rational design
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On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC80 value of compounds 8c, 8i and 8n against C. albicans is 0.001 μg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.
- Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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supporting information; experimental part
p. 5965 - 5969
(2010/07/04)
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- Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory t cells in autoimmune diseases
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The lymphocyte K+ channel Kv1.3 constitutes an attractive pharmacological target for the selective suppression of terminally differentiated effector memory T (TEM) cells in T cell mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Unfortunately, none of the existing small molecule Kv1.3 blockers is selective, and many of them, such as correolide, 4-phenyl-4-[3-(methoxyphenyl)-3-oxo-2- azapropyl] cyclohexanone, and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. By further exploring the structure activity relationship around Psora-4 through a combination of traditional medicinal chemistry and whole-cell patch-clamp, we identified a series of new phenoxyalkoxypsoralens that exhibit 2- to 50-fold selectivity for Kv1.3 over Kv1.5, depending on their exact substitution pattern. The most potent and "druglike" compound of this series, 5-(4-phenoxybutoxy)psoralen (PAP-1), blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+, Ca2+, and Cl- channels. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulators. Copyright
- Schmitz, Alexander,Sankaranarayanan, Ananthakrishnan,Azam, Philippe,Schmidt-Lassen, Kristina,Homerick, Daniel,Haensel, Wolfram,Wulff, Heike
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p. 1254 - 1270
(2007/10/03)
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- Design, synthesis, antibacterial and QSAR studies of benzimidazole and imidazole chloroaryloxyalkyl derivatives
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In view of obtaining some potential antibacterial compounds, we have described synthesis of some chloroaryloxyalkyl imidazole and benzimidazole derivatives. The relevant step in the synthetic sequence was the initial condensation of 4-chloro or 2,4-dichlorophenol with 1, n-dibromoalkanes (n = 2, 4, 5) to provide compounds 3a-f in sufficient yields. The subsequent condensation of 3a-f with some imidazole derivatives and benzimidazole afforded products 4a-l and 5a-e in good yields. Some of compounds 4a-l as well as 5a-e were tested in vitro against Salmonella typhi O-901 and Staphylococcus aureus A 15091. Compounds 4a and 4c showed considerable bactericidal activities against tested bacteria. Compound 4b showed significant activity against S. aureus A 15091 but was inactive against S. typhi O-901. Other compounds showed intermediate activities against S. aureus A 15091 but most of them were inactive against S. typhi O-901. Semiempirical AM1 calculations showed that negative electrostatic potentials around oxygen of the phenoxy and nitrogen of the imidazole moieties have direct effect on the antibacterial activity towards S. aureus A 15091. In QSAR analysis, different electronic, topologic, functional groups and physicochemical descriptors were calculated for each molecule and a three parametric equation was found between the log MIC and HOMO energy, hydration energy and number of primary carbon atoms of the molecules.
- Khalafi-Nezhad,Soltani Rad,Mohabatkar,Asrari,Hemmateenejad
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p. 1931 - 1938
(2007/10/03)
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- Carboxylic acids and skeletal muscle chloride channel conductance: Effects on the biological activity induced by the introduction of an aryloxyalkyl group α to the carboxylic function of 4-chloro-phenoxyacetic acid
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2-(4-Chloro-phenoxy)propanoic and 2-(4-chloro-phenoxy)butanoic acids are compounds known to block chloride membrane conductance in rat striated muscle by interaction with a specific receptor. In the present study, a series of chiral analogues has been prepared and tested to evaluate the influence of a second aryloxy moiety introduced in the side-chain at a variable distance from the stereogenic centre. The results show that this chemical modification is detrimental for biological activity which, however, is increased by lengthening the alkyl chain up to three methylenic groups, then decreases to remain constant in the next analogues of the series. A possible explanation for this is proposed on the basis of steric effects and/or different approach of the molecules to the receptor.
- Carbonara, Giuseppe,Fracchiolla, Giuseppe,Loiodice, Fulvio,Tortorella, Paolo,Conte-Camerino, Diana,De Luca, Annamaria,Liantonio, Antonella
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p. 749 - 754
(2007/10/03)
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- Carboxylic acid derivatives, processes for the preparation thereof, the use thereof, and pharmaceutical compositions which contain these compounds
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This invention relates to carboxylic acid derivatives and their use thereof. The compounds are useful in treatment of various diseases such as diabetes, prediabetic conditions, adipositas ailments or atherosclerosis.
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