- Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation
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Amyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. In vitro studies showed that compounds 25–30 (20 μM) with N-methylation of the quinolone ring effectively inhibited Aβ1-42 aggregation by 84.7%–99.5% and tau aggregation by 71.2%–101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aβ1-42 and tau, inhibit Aβ1-42 β-sheets formation, and prevent tau aggregation in living cells.
- Lv, Peng,Xia, Chun-Li,Wang, Ning,Liu, Zhen-Quan,Huang, Zhi-Shu,Huang, Shi-Liang
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- Bistacrines as potential antitrypanosomal agents
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Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.
- Schmidt, Ines,G?llner, Sarah,Fu?, Antje,Stich, August,Kucharski, Anna,Schirmeister, Tanja,Katzowitsch, Elena,Bruhn, Heike,Miliu, Alexandra,Krauth-Siegel, R. Luise,Holzgrabe, Ulrike
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- Heterocycle-to-heterocycle route to quinoline-4-amines: Reductive heterocyclization of 3-(2-nitrophenyl)isoxazoles
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A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc using a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
- Coffman, Keith C.,Duong, Vy,Bagdasarian, Alex L.,Fettinger, James C.,Haddadin, Makhluf J.,Kurth, Mark J.
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p. 7651 - 7657
(2015/04/22)
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- Synthesis of 4-methyl-2,3-disubstituted quinoline scaffolds via environmentally benign Fe(iii) catalysed sequential condensation, cyclization and aromatization of 1,3-diketone and 2-ethynylaniline
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Environmentally benign Fe(iii)-catalysed sequential condensation, cyclization and aromatization of 1,3-diketone and 2-ethynylaniline derivatives to the substituted quinoline scaffolds with good to excellent yield in shorter reaction time is described. This journal is
- Sivaraman, Mahalingam,Perumal, Paramasivan T.
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p. 52060 - 52066
(2014/12/10)
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- Sulfuric acid-modified PEG-6000 (PEG-OSO3H): An efficient, bio-degradable and reusable polymeric catalyst for the solvent-free synthesis of poly-substituted quinolines under microwave irradiation
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Sulfuric acid-modified polyethylene glycol 6000 (PEG-OSO3H) is applied as an efficient and eco-friendly polymeric catalyst for Friedlaender synthesis of poly-substituted quinolines from 2-aminoaryl ketones (or anthranilonitrile) and carbonyl compounds possessing a reactive methylene group under microwave irradiation and solvent-free conditions. The reactions are completed in short times, and the products are obtained in good to excellent yields. The Royal Society of Chemistry.
- Hasaninejad, Alireza,Zare, Abdolkarim,Shekouhy, Mohsen,Ameri-Rad, Javad
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experimental part
p. 958 - 964
(2011/05/12)
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- Synthesis and biological testing of pyrano[2,3-a]acridinones
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The synthesis of 12-amino-7a and 12-hydroxy-2-arylpyrano[2,3-a]acridin-4-ones 7b and 19 via the von Strandtmann flavone annelation procedure is described, in which the pyranone ring is formed by the reaction of a β-ketosulfoxide 13, 18 with an aromatic aldehyde.
- Drewe, Jacqueline A.,Groundwater, Paul W.
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p. 601 - 605
(2007/10/03)
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- Method of reducing a carbonyl containing acridine
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A method of reducing a carbonyl containing acridine of the formula STR1 where n is 1, 2 or 3; X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, trifluoromethyl, or NR3 R4 where R3 and R4 are independently hydrogen or loweralkyl; R is hydrogen or loweralkyl and R1 is hydrogen, loweralkyl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, furylloweralkyl, thienylloweralkyl, oxygen-bridged arylloweralkyl, oxygen-bridged diarylloweralkyl, oxygen-bridged furylloweralkyl or oxygen-bridged thienylloweralkyl, is disclosed.
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- A Novel Synthesis of the Isoxazoloacridine Ring System
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The Schmidt reaction of 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (1) is described.In addition to the expected isomeric lactams, 3-phenyl-5,6,7,8-tetrahydro-4H-isoxazoloazepin-4-one (3) and 7,8-dihydro-3-phenyl-4H-isoxazoloazepin-5(6H)-one (4), 4-amino-3-phenyl-1,2-benzisoxazole (5) was isolated, along with 4,5-dihydro-3H-isoxazoloacridine (6).Possible mechanisms for the formation of these products are discussed and some chemistry of the little-known ring system represented by 6 is also described.
- Shutske, Gregory M.
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p. 1617 - 1621
(2007/10/02)
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- 9-Amino-1,2,3,4-tetrahydroacridin-1-ols: Synthesis and evaluation as potential Alzheimer's disease therapeutics
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The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease - the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (±)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (±)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 μM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.
- Shutske,Pierrat,Kapples,Cornfeldt,Szewczak,Huger,Bores,Haroutunian,Davis
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p. 1805 - 1813
(2007/10/02)
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- 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds
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There are disclosed compounds having the formula STR1 wherein n is 1, 2 or 3; X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl, NHCOR2 where R2 is loweralkyl, or NR3 R4 where R3 and R4 are independently hydrogen or loweralkyl; R is hydrogen or loweralkyl; R1 is hydrogen, loweralkyl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, furylloweralkyl, thienylloweralkyl, oxygen-bridged arylloweralkyl, oxygen-bridged diarylloweralkyl, oxygen-bridged furylloweralkyl or oxygen-bridged thienylloweralkyl; Y is C=O or CR5 OH where R5 is hydrogen or loweralkyl; Z is CH2 or C=CR6 R7 where R6 and R7 are independently hydrogen or loweralkyl; or Y and Z taken together is CR5 =CH where CR5 and CH correspond to Y and Z respectively; an optical antipode thereof, or a pharmaceutically acceptable acid addition salt thereof, which are useful for enhancing memory, methods for synthesizing them, and pharmaceutical compositions comprising an effective memory enhancing amount of such a compound.
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- 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds
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There are disclosed compounds having the formula STR1 wherein X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, nitro, NHCOR2 wherein R2 is loweralkyl, or a group of the formula NR3 R4 wherein R3/s
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