- Polymer-supported oligoethylene glycols as heterogeneous multifunctional catalysts for nucleophilic substitution
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We investigated various structurally modified polystyrene-supported oligoethylene glycols (PSoligoEG) in order to find an optimized PSoligoEG by examining the dependence of their catalytic activity on the oligoethylene glycol chain length and the loading level of the oligoethylene glycol portion on the polystyrene support. From this, we found that the PSpentaEG with the highest pentaEG loading had the best catalytic efficacy among the various PSoligoEGs in nucleophilic substitutions. This PSpentaEG absorbed both polar aprotic solvents, such as DMSO, DMF, and acetonitrile, as well as protic media, such as tert-amyl alcohol and aqueous acetone, and swelled considerably. To expand the scope of the PSpentaEG as a heterogeneous catalyst for diverse nucleophilic displacement reactions, we carried out the thioacetoxylation, nitrilation, azidation, iodination, bromination, chlorination, and methoxylation using the corresponding alkali metal salts in the presence of PSpentaEG in various solvents; all the reactions proceeded smoothly, affording the corresponding products in high yields.
- Jadhav, Vinod H.,Jeong, Hwan-Jeong,Lim, Seok Tae,Sohn, Myung-Hee,Song, Choong Eui,Kim, Dong Wook
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Read Online
- Structural modifications in the distal, regulatory region of histamine H3 receptor antagonists leading to the identification of a potent anti-obesity agent
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A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H3 receptor (H3R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H3R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on H3R affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the H3R (Ki = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H3 receptor. While its structural replacement to piperidine is also tolerated for H3R binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H3R, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.
- Szczepańska, Katarzyna,Pockes, Steffen,Podlewska, Sabina,H?ring, Carina,Mika, Kamil,Latacz, Gniewomir,Bednarski, Marek,Siwek, Agata,Karcz, Tadeusz,Nagl, Martin,Bresinsky, Merlin,M?nnich, Denise,Seibel, Ulla,Kuder, Kamil J.,Kotańska, Magdalena,Stark, Holger,Elz, Sigurd,Kie?-Kononowicz, Katarzyna
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supporting information
(2020/12/07)
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- Synthesis of Medium-Ring-Sized Benzolactams by Using Strong Electrophiles and Quantitative Evaluation of Ring-Size Dependency of the Cyclization Reaction Rate
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Benzolactams with medium-sized rings were synthesized via the electrophilic aromatic substitution reaction of carbamoyl cations (R1R2N+═C═O) in good to high yields without dilution. These reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring formation, compared to five- or six-membered ring formation. The order of reaction rates of formation of cyclic benzolactams is six- > five- > seven- > eight- > nine-membered ring at 25 °C. The present reaction provides a route to eight- A nd nine-membered benzolactams.
- Kurouchi, Hiroaki,Ohwada, Tomohiko
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p. 876 - 901
(2019/12/30)
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- Discovery of benzotriazole-azo-phenol/aniline derivatives as antifungal agents
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A series of benzotriazole-azo-phenol/aniline derivatives were prepared and evaluated for their antifungal activities against six phytopathogenic fungi such as Fusarium graminearum, Fusarium solani, Alternaria alternate, Valsa mali, Botrytis cinerea, and Curvularia lunata. Among them, compounds IIf, IIn, and IIr showed a broad-spectrum of potent antifungal activities. Especially some compounds displayed 3.5–10.8 folds more potent activities than carbendazim against A. alternata and C. lunata. Notably, compounds IIc, IIm, and IIr exhibited good protective and therapeutic effects against B. cinerea at 200 μg/mL. Their structure-activity relationships were also discussed.
- Lv, Min,Ma, Jingchun,Li, Qin,Xu, Hui
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supporting information
p. 181 - 187
(2017/12/04)
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- Synthesis and antibacterial activity of 3-benzylamide derivatives as FtsZ inhibitors
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The emergence and spread of multidrug-resistant strains of the human pathological bacteria are generating a threat to public health worldwide. In the current study, a series of PC190723 derivatives was synthesized and investigated for their antimicrobial activity. The compounds exhibited good activity against several Gram-positive bacteria as determined by comparison of diameters of the zone of inhibition of test compounds and standard antibiotics. Compound 9 with a fluorine substitution on the phenyl ring showed the best antibacterial activity in the series against M. smegmatis with the zone ratio of 0.62, and against S. aureus with the zone ratio of 0.44. The results from this study indicate that based on the unique 3-methoxybenzamide pharmacophore, compound 9 may represent a promising lead candidate against Gram-positive bacteria that are worthy of further investigation
- Hu, Zhongping,Zhang, Shasha,Zhou, Weicheng,Ma, Xiang,Xiang, Guangya
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supporting information
p. 1854 - 1858
(2017/04/04)
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- Hydrogen-Bonded Homoleptic Fluoride-Diarylurea Complexes: Structure, Reactivity, and Coordinating Power
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Hydrogen bonding with fluoride is a key interaction encountered when analyzing the mode of action of 5′-fluoro-5′-deoxyadenosine synthase, the only known enzyme capable of catalyzing the formation of a C-F bond from F-. Further understanding of the effect of hydrogen bonding on the structure and reactivity of complexed fluoride is therefore important for catalysis and numerous other applications, such as anion supramolecular chemistry. Herein we disclose a detailed study examining the structure of 18 novel urea-fluoride complexes in the solid state, by X-ray and neutron diffraction, and in solution phase and explore the reactivity of these complexes as a fluoride source in SN2 chemistry. Experimental data show that the structure, coordination strength, and reactivity of the urea-fluoride complexes are tunable by modifying substituents on the urea receptor. Hammett analysis of aryl groups on the urea indicates that fluoride binding is dependent on σp and σm parameters with stronger binding being observed for electron-deficient urea ligands. For the first time, defined urea-fluoride complexes are used as fluoride-binding reagents for the nucleophilic substitution of a model alkyl bromide. The reaction is slower in comparison with known alcohol-fluoride complexes, but SN2 is largely favored over E2, at a ratio surpassing all hydrogen-bonded complexes documented in the literature for the model alkyl bromide employed. Increased second-order rate constants at higher dilution support the hypothesis that the reactive species is a 1:1 urea-fluoride complex of type [UF]- (U = urea) resulting from partial dissociation of the parent compound [U2F]-. The dissociation processes can be quantified through a combination of UV and NMR assays, including DOSY and HOESY analyses that illuminate the complexation state and H-bonding in solution.
- Pfeifer, Lukas,Engle, Keary M.,Pidgeon, George W.,Sparkes, Hazel A.,Thompson, Amber L.,Brown, John M.,Gouverneur, Véronique
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supporting information
p. 13314 - 13325
(2016/10/22)
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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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- Organocatalysis of nucleophilic substitution reactions by the combined effects of two promoters fused in a molecule: Oligoethylene glycol substituted imidazolium salts
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Oligoethylene glycol substituted imidazolium salts were synthesized as promoters for a range of SN2 reactions, and their efficiency was examined. These tailor-made organic promoters enhanced the nucleophilicity of alkali metal salts significantly through the combined effects of two promoters (oligoethylene glycols and imidazolium salts) in a single molecule. The effects of the oligoethylene glycol side chain length, ionic liquid anions, nucleophiles, and substrates were investigated systematically. [hexaEGmim][OMs] and [dihexaEGim][OMs] showed the highest efficiency for SN2 reactions using alkali metal salts. The role of the terminal hydroxyl groups of the oligoethylene glycol moiety was assessed by examining the relative S N2 yields of chlorination and bromination. The results showed that the hydrogen bonding strength of the hydroxyl groups with the nucleophile is very important. The mechanism for the excellent promotion of SN2 reactions by oligoEGILs was examined by quantum chemical calculations. The results showed that the oxygen atoms in the oligoethylene glycol portion and the ionic liquid anion act on the counter cation K+ or Na+ as a Lewis base, to enhance the reactivity of the metal salts significantly.
- Jadhav, Vinod H.,Kim, Ju-Young,Chi, Dae Yoon,Lee, Sungyul,Kim, Dong Wook
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p. 533 - 542
(2014/01/06)
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- NOVEL ANTIMICROBIAL COMPOUNDS
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A new class of biotin protein ligase (BPL) inhibitors that have antibacterial activity against multiple Staphylococcus aureus isolates, including clinically important methicillin-resistant S. aureus (MRSA) are disclosed that are non-toxic.
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Page/Page column 17
(2013/04/10)
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- Oligoethylene glycols as highly efficient mutifunctional promoters for nucleophilic-substitution reactions
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Herein, we report the promising use of n-oligoethylene glycols (oligoEGs) as mutifunctional promoters for nucleophilic-substitution reactions employing alkali metal salts. Among the various oligoEGs tested, pentaethylene glycol (pentaEG) had the most efficient catalytic activity. In particular, when compared with other nucleophiles examined, a fluorine nucleophile generated from CsF was significantly activated by the pentaEG promoter. We also performed various facile nucleophilic-displacement reactions, such as the halogenation, acetoxylation, thioacetoxylation, nitrilation, and azidation of various substrates with potassium halides, acetate, thioacetate, cyanide, and sodium azide, respectively, in the presence of the pentaEG promoter. All of these reactions provided their desired products in excellent yields. Furthermore, the combination of pentaEG and a tert-alcohol medium showed tremendous efficiency in the nucleophilic-displacement reactions (fluorination and methoxylation) of base-sensitive substrates with basic nucleophiles (cesium fluoride and potassium methoxide, respectively). The catalytic role of oligoEGs was examined by quantum-chemical methods. The oxygen atoms in oligoEGs were found to act as Lewis bases on the metal cations to produce the "flexible" nucleophile, whereas the two terminal hydroxy (OH) groups acted as "anchors" to orientate the nucleophile and the substrate into an ideal configuration for the reaction. The EG race: OligoEGs, such as pentaethylene glycol (pentaEG), act as mutifunctional promoters for nucleophilic-substitution reactions with the corresponding alkali-metal salts. The combination of pentaEG and a tert-alcohol media system showed tremendous efficiency in the fluorination and methoxylation of base-sensitive substrates by using the corresponding basic nucleophiles (see figure). Copyright
- Jadhav, Vinod H.,Jang, Seung Ho,Jeong, Hwan-Jeong,Lim, Seok Tae,Sohn, Myung-Hee,Kim, Ju-Young,Lee, Sungyul,Lee, Ji Woong,Song, Choong Eui,Kim, Dong Wook
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experimental part
p. 3918 - 3924
(2012/06/01)
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- Fragmentations observed in the reactions of α-methoxy-γ- alkoxyalkyl iodide substrates with super-electron-donors derived from 4-DMAP and N-methylbenzimidazole
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Reactions of super-electron-donors (SEDs) derived from 4- dimethylaminopyridine and from N-methylbenzimidazole with α-methoxy- γ-alkoxyalkyl iodides lead to liberation of the γ-alkoxy groups as their alcohols. This is consistent with generation of alkyl radicals from the alkyl halide precursors, and trapping of these radicals by the radical-cation of the SED, followed by a heterolytic fragmentation.
- Sword, Ryan,Baldwin, Luke A.,Murphy, John A.
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experimental part
p. 3560 - 3570
(2011/06/20)
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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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- 7-NONSUBSTITUTED INDOLE MCL-1 INHIBITORS
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Compounds of formula (I) which inhibit the activity of anti-apoptotic Mcl-1 protein, compositins containing the compounds, and methods of treating diseases involving overexpressed or unregulated Mcl-1 protein are disclosed.
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Page/Page column 76
(2008/12/08)
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- Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: Significantly enhanced reactivity of alkali metal fluorides and improved selectivity
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(Chemical Equation Presented) Although protic solvents are generally not preferred for nucleophilic displacement reactions because of their partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce its reactivity, we recently reported a remarkably beneficial effect of using tertiary alcohols as a reaction media for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with [ 18F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate further the influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxy substrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation of a tert-alcohol solvated fluoride, and hydrogen bonding between the sulfonate leaving group and the tert-alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reaction in the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (5) and N-5-bromopentanoyl-3,4- dimethoxyaniline (8) with Bu4N+F- in a tert-alcohol afforded the corresponding fluoro products in much higher yield than obtained by the conventional methods using dipolar aprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers, and cyclic adducts.
- Dong, Wook Kim,Jeong, Hwan-Jeong,Seok, Tae Lim,Sohn, Myung-Hee,Katzenellenbogen, John A.,Dae, Yoon Chi
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p. 957 - 962
(2008/09/18)
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- A new class of SN2 reactions catalyzed by protic solvents: Facile fluorination for isotopic labeling of diagnostic molecules
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Aprotic solvents are usually preferred for the SN2 reactions, because nucleophilicity and hence SN2 reactivity are severely retarded by the influence of the partial positive charge of protic solvents. In this work, we introduce a remarkable effect of using tertiary alcohols as a reaction medium for nucleophilic fluorination with alkali metal fluorides. In this novel synthetic method, the nonpolar protic tert-alcohol enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly increasing the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes, alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. The great efficacy of this method is a particular advantage in labeling radiopharmaceuticals with [18F]fluorine (t1/2 = 110 min) for positron emission tomographic (PET) imaging, and it is illustrated by the synthesis of four [ 18F]fluoride-radiolabeled molecular imaging probes-[ 18F]FDG, [18F]FLT, [18F]FP-CIT, and [ 18F]FMISO-in high yield and purity and in shorter times compared to conventional syntheses.
- Kim, Dong Wook,Ahn, Doo-Sik,Oh, Young-Ho,Lee, Sungyul,Kil, Hee Seup,Oh, Seung Jun,Lee, Sang Ju,Kim, Jae Seung,Ryu, Jin Sook,Moon, Dae Hyuk,Chi, Dae Yoon
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p. 16394 - 16397
(2007/10/03)
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- (±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines as a new class of specific bradycardic agents
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A series of (±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were examined in isolated guinea-pigs' right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1, led to the identification of compound 11e as a potent and specific bradycardic agent.
- Kubota, Hideki,Kakefuda, Akio,Watanabe, Toshihiro,Taguchi, Yasuko,Ishii, Noe,Masuda, Noriyuki,Sakamoto, Shuichi,Tsukamoto, Shin-Ichi
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p. 2155 - 2158
(2007/10/03)
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- Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
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A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
- Bymaster,Beedle,Findlay,Gallagher,Krushinski,Mitchell,Robertson,Thompson,Wallace,Wong
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p. 4477 - 4480
(2007/10/03)
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- Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials
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A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.
- Jensen,Ager,Bliss,Canfield,Kotecka,Rieckmann,Terpinski,Jacobus
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p. 3925 - 3931
(2007/10/03)
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- New naphthyloxyalkyl β-diketone and 3,5-dimethylisoxazole derivatives as potential antiviral agents
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Ten new compounds having 3-[(2-naphthyloxy)alkyl]-2,4-pentanedione and 4-[(2-naphthyloxy)alkyl]-3,5-dimethylisoxazole structures were synthesized and their cytotoxicities and antiviral activities investigated. 3-[6-(2-Naphthyloxy)hexyl]-2,4-pentandione possessing inhibitory activity on the replication of both adenovirus type 5 and poliovirus type 1 at 20 μg/ml was the most active compound in the series.
- Balkan,Akgun,Parali,Ertan,Acikgoz,Ustacelebi
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p. 589 - 594
(2007/10/03)
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- Photolyses of (3-Naphthoxypropyl)-, (4-Naphthylbutyl)-, and (4-Naphthyl-4-oxobutyl)cobaloxime
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The cobalt-carbon bond of the titled compounds is photochemically cleaved to generate an organoradical and a cobaloxime(II) radical pair. 3-(1- or 2-naphtoxy)propyl, 4-(1- or 2-naphthyl)butyl, and 4-(1-or 2-napthyl)-4-oxobutyl radicals thus formed undergo three types of reactions: (a) hydrogen abstraction to give a saturated terminal, (b) hydrogen elimination to give a terminal olefin, and (c) substitution on the naphthalene ring.In benzene and radicals follow process b exclusively (the radicals from (3-(2-napthoxy)propyl)cobaloxime (1a), (3-(1-napthoxy)propyl)cobaloxime (2a), and (4-(1-napthyl)butyl)cobaloxime (2 b)) or preferentially (the radicals from (4-(2-napthyl)butyl)cobaloxime (1 b), (4-(2-napthyl)-4-oxobutyl)cobaloxime (1c), and 4-(1-napthyl)-4-oxobutyl)cobaloxime (2c)).In chloroform, process a becomes important to the extent as the sum of the other two processes.In water-acetonitril (4:1), process c becomes important and even takes precedence of others for the radicals from 1b and 1c.This feature is accounted for by the folding of the side chain of hydrophobic radicals.Encapsulation of the radicals in β-cyclodextrin stimulates process c except for the case of the radical from 2c.In the case of cobaloxime 2c, α-cyclodextrin does not effect the partition process of the intermediate radical.This feature is accounted for by the shallow inclusion of the radical due to the hydrogen bonding as depicted in Figure 1d.
- Tada, Masaru,Hiratsuka, Mitsunori,Goto, Hiroyuki
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p. 4364 - 4370
(2007/10/02)
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- ARALKOXY AND ARYLOXYALKOXY KOJIC ACID DERIVATIVES
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This invention relates to substituted aralkoxy and aryloxyalkoxy kojic acid derivatives, which are useful as leukotriene D. sub.4 (LTD 4) inhibitors and therefore useful in the treatment of allergies, inflammatory conditions, and coronary vasoconstriction.
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