- Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy
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Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.
- Yeon, Seul Ki,Choi, Ji Won,Park, Jong-Hyun,Lee, Ye Rim,Kim, Hyeon Jeong,Shin, Su Jeong,Jang, Bo Ko,Kim, Siwon,Bahn, Yong-Sun,Han, Gyoonhee,Lee, Yong Sup,Pae, Ae Nim,Park, Ki Duk
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supporting information
p. 232 - 244
(2017/12/08)
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- Synthesis and structure-activity studies of side chain analogues of the anti-tubercular agent, Q203
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The anti-tubercular activity of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (Q203) is modified by varying its side chain. In this study, we synthesized Q203 analogues with different side
- Kang, Sunhee,Kim, Young Mi,Kim, Ryang Yeo,Seo, Min Jung,No, Zaesung,Nam, Kiyean,Kim, Sanghee,Kim, Jaeseung
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p. 807 - 815
(2016/10/24)
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- Benzyloxybenzylammonium chlorides: Simple amine salts that display anticonvulsant activity
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Several antiepileptic drugs exert their activities by inhibiting Na + currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar′) modulate Na+ currents. We, and others, have reported that compound
- Lee, Hyosung,Gold, Alexander S.,Yang, Xiao-Fang,Khanna, Rajesh,Kohn, Harold
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supporting information
p. 7655 - 7662
(2014/01/06)
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- Selective para-cyanation of alkoxy- and benzyloxy-substituted benzenes with potassium ferricyanide promoted by copper(II) nitrate and iodine
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A simple method was developed for selective para-cyanation of alkoxy- and benzyloxy-substituted benzenes with 0.5 equivalents of potassium ferricyanide, 0.8 equivalants of copper(II) nitrate and 0.5 equivalents of iodine in acetonitrile. Among various phenyl carbon-hydrogen bonds, those at the para-position with regard to the alkoxy or benzyloxy groups were selectively cyanated in 20% to 87% yields (23 examples). The present method uses commercially available reagents, and can be performed on a ten gram-scale. Interestingly, methoxybenzene was cyanated in 32% yield in the absence of potassium ferricyanide, which suggests that the nitrile group of a part of the product is possibly from the solvent acetonitrile. Copyright
- Ren, Yunlai,Yan, Mengjie,Zhao, Shuang,Wang, Jianji,Ma, Junying,Tian, Xinzhe,Yin, Weiping
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supporting information
p. 2301 - 2308
(2012/11/06)
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- Merging the structural motifs of functionalized amino acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities
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Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3′′-fluoro) benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.
- Salomé, Christophe,Salomé-Grosjean, Elise,Stables, James P.,Kohn, Harold
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supporting information; experimental part
p. 3756 - 3771
(2010/07/16)
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- Second-generation tags for fluorous chemistry exemplified with a new fluorous Mitsunobu reagent
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(Chemical Equation Presented) A new fluorous DEAD reagent bearing two perfluoro-tert-butyloxy groups with propylene spacers shows excellent promise for use in fluorous Mitsunobu reactions. Pure target products were obtained in good yields after removing fluorous byproducts by FSPE. The new reagent serves as a prototype for a greener second generation of fluorous reagents bearing tags that are not expected to degrade in the environment to compounds that are highly persistent or that bioaccumulate in higher organisms.
- Chu, Qianli,Henry, Christopher,Curran, Dennis P.
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supporting information; experimental part
p. 2453 - 2456
(2009/05/26)
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- Second generation fluorous DEAD reagents have expanded scope in the Mitsunobu reaction and retain convenient separation features
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First generation fluorous DEAD reagent bis(perfluorohexylethyl)azo dicarboxylate (C6F13(CH2)2O 2-CN=NCO2(CH2)2C6F13, F-DEAD-1) has been shown to underperform relative to diisopropylazodicarboxylate in difficult Mitsunobu reactions involving hindered alcohols or less acidic pronucleophiles (phenols). Two new second generation fluorous reagents bearing propylene spacers instead of the ethylene spacers show expanded reaction scope while retaining the easy fluorous separation features. Byproducts from "half fluorous" reagent perfluorooctylpropyl tert-butyl azo dicarboxylate (C8F17(CH2)3O 2CN=NCO2tBu, F-DEAD-2) can be removed by fluorous flash chromatography, and byproducts from bis(perfluorohexylpropyl)azo dicarboxylate (C6F13(CH2)3O 2CN=NCO2(CH2)3C6F 13, F-DEAD-3) can be removed by fluorous solid-phase extraction. The new reagents promise to provide general and complementary solutions for separation problems in Mitsunobu reactions without restricting reaction scope.
- Dandapani, Sivaraman,Curran, Dennis P.
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p. 8751 - 8757
(2007/10/03)
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- Separation tagging with cyclodextrin-binding groups: Mitsunobu reactions with bis-(2-(1-adamantyl)ethyl) azodicarboxylate (BadEAD) and bis-(1-adamantylmethyl) azodicarboxylate (BadMAD)
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A new method for separation tagging with cyclodextrin-binding groups is introduced and is exemplified in the context of the Mitsunobu reaction with adamantyl tags. HPLC experiments showed that molecules containing adamantyl groups were especially well retained on Sumichiral OA7500 β-methylated cyclodextrin bonded silica columns relative to many other types of molecules. Two new Mitsunobu reagents, bis-(1-adamantylmethyl) azodicarboxylate (BadMAD) and bis-(2-(1-adamantyl)ethyl) azodicarboxylate (BadEAD), were prepared, used in typical Mitsunobu reactions and separated with both β-methylated cyclodextrin bonded silica and standard silica.
- Dandapani, Sivaraman,Newsome, Jeffery J.,Curran, Dennis P.
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p. 6653 - 6656
(2007/10/03)
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- Selective and Potent Monoamine Oxidase Type B Inhibitors: 2-Subtituted 5-Aryltetrazole Derivatives
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Twenty new 2-(cyanoalkyl)tetrazoles (15 and 16) and twenty new 2-(hydroxyalkyl)tetrazoles (17 and 18) were synthesized and investigated in vitro for their abilities to inhibit selectivity rat brain monoamine oxidase (MAO) B over MAO A.Most of then were MAO B inhibitors and those bearing a sunstituted 4-(arylmethoxy)phenyl group in the position 5 of the tetrazole ring had IC50 values between 8 νM for 18d and 2 nM for 16a (30 nM for lazabemide) with a selectivity toward MAO B of 37000 for 16a.The reversibility of their inhibitory activity was demonstrated by in vitro dialysis tests.The 5--2-(2-cyanoethyl)-tetrazole (16a) its derivative 16h and the 5--2-(2-hydroxyethyl)-tetrazole (18a) and its derivative 18h were found to be potent, in vitro selective, and competitive MAO B inhibitors.Tetrazole 16a can be considered one of the most active and selective competitive MAO B inhibitors known up to now.This compound was selected for ex vivo experiments and shown to be a strong and reversible MAO B inhibitor with a short duration of action after oral administration at 5 mg/kg.The structure-activity approach gives rise to the great inportance of lipophilicity over electronic effects of the compounds in these series.
- Lebreton, Luc,Curet, Olivier,Gueddari, Salach,Mazouz, Fathi,Bernard, Suzanne,et al.
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p. 4786 - 4792
(2007/10/03)
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- Hypolipidemic analogues of ethyl 4 benzyloxybenzoate
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A series of compounds related to ethyl 4-benzyloxybenzoate was synthesized and evaluated for potential hypolipidemic activity in rats. Structure-activity relationships are discussed in terms of cholesterol-lowering activity together with effects on body weight gain and liver lipids. A number of the compounds inhibited cholesterol and free fatty acid biosynthesis from [1-14C]acetate in rat liver slices in vitro. Ethyl 4-benzyloxybenzoate, ethyl 4-benzyloxybenzoic acid, ethyl 4-p-bromobenzyloxybenzoate, and ethyl 4-o-methoxybenzyloxyphenyl acetate exhibited the most favorable spectrum of activity.
- Baggaley,Fears,Hindley,Morgan,Murrell,Thorne
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p. 1388 - 1393
(2007/10/05)
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