- Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents
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The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human β-secretase (hBACE-1), and β-amyloid (Aβ-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 μM), hBACE-1 (43.7% at 50 μM), and Aβ-aggregation (24.9% at 10 μM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes-acetylcholinesterase and β-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: β-secretase and Aβ-aggregation.
- Panek, Dawid,Wi?ckowska, Anna,Pasieka, Anna,Godyń, Justyna,Jończyk, Jakub,Bajda, Marek,Knez, Damijan,Gobec, Stanislav,Malawska, Barbara
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q5, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 68
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (Formula (I)), including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 72
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (Formula (I)), including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 69-70
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have one of the following structures (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3 and Z1 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 97
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Ql, Q2, Rl, R2 and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 58
(2010/04/28)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R1, R2 and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 102
(2010/12/17)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2 and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 58
(2010/04/28)
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- TREATMENT OF URINARY TRACT INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS
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A method for treating a urinary tract infection in a mammal in need thereof is disclosed, the method comprising administering to the mammal an effective amount of an antibacterial aminoglycoside compound.
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Page/Page column 149
(2010/12/17)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds of structure (I): having antibacterial activity are disclosed, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R8 and R9 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 142
(2009/06/27)
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- Isomerization of cyclic ethers having a carbonyl functional group: New entries into different heterocyclic compounds
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Oxiranes (epoxides) and oxetanes having a carbonyl functional group are chemoselectively isomerized to different heterocyclic compounds via Lewis acid-promoted 1,6- and 1,7-intramolecular nucleophilic attacks of the carbonyl oxygen on the electron-deficient carbon neighboring the oxonium oxygen: for example, cyclic imides to bicyclic acetals, esters to bicyclic orthoesters, sec-amides to 4,5-dihydrooxazole or 5,6-dihydro-4H-1,3-oxazines, and tert-amides to bicyclic acetals or azetidines. The intramolecular attack of a 1,5-positioned carbonyl oxygen predominantly results in a propagating-end isomerization polymerization. On the other hand, cyclic ethers having a 1,8- or farther positioned carbonyl group undergo conventional ring-opening polymerization. A tetrahydrofuran (oxolane) ring does not open, even with a 1,6-positioned carbonyl group.
- Kanoh, Shigeyoshi,Naka, Masashi,Nishimura, Tomonari,Motoi, Masatoshi
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p. 7049 - 7064
(2007/10/03)
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- Radiosensitizers of hypoxic mammalian cells. 1-(hydroxyaminoalkyl)-substituted nitroimidazoles
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A series of novel 1-(hydroxyaminoalkyl)-substituted nitroimidazoles has been synthesized as potential radiosensitizers for hypoxic mammalian cells. These compounds were synthesized via N-(hydroxyalkyl)phthalimide nitroimidazole intermediates which, on reaction with hydrazine hydrate, yielded the corresponding amines. The intermediates were prepared by reacting the epoxide derived from nitroimidazole with phthalimide and/or the epoxide derived from phthalimide with the nitroimidazole. The method was used successfully for the preparation of 2-, 4- and 5-nitroimidazole derivatives. In a modification of this procedure, 1-(2-aminoethyl)-2-nitroimidazole has been prepared by a new route which avoids the use of aziridine. These agents were tested for cytotoxicity and radiosensitizing ability in vitro using Chinese hamster V79 cells. All of the 2-nitroimidazoles tested showed toxicity similar to that previously reported for misonidazole and Ro 03-8799 (1-(2-hydroxy-3-piperidinopropyl)-2-nitroimidazole), two compounds currently undergoing clinical evaluation. In addition, all the novel primary amines were shown to function as hypoxic cell radiosensitizers. The 2-nitroimidazole derivatives were the most efficient compounds to be examined and showed at least as much activity as misonidazole.
- Ahmed,Stratford,Jenkins
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p. 1763 - 1768
(2007/10/02)
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