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[ CAS No. 1122-58-3 ] {[proInfo.proName]}

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Product Citations

Eduardo Ramirez ; DOI:

Abstract: Alzheimer’s (AD) and Parkinson’s (PD) are the most common debilitating disorders to affect the geriatric population. There are two pathological hallmarks which correlate with the manifestation of AD: the first is the formation amyloid-β plaques (Aβ plaques) in the extracellular space and the second is the aggregation of hyperphosphorylated tau protein (p-tau) which develops into neurofibrillary tangles (NFTs) in the interneuron. PD results from the misfolding of α-synuclein (α-syn) which then aggregates to form Lewy bodies. In over 50% of AD cases aggregated α-syn_x0002_containing Lewy bodies are presently displayed. My research projects focus on the dual targeting of small molecules to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to reduce the spread of AD and related dementias. Not very many drug discovery programs focus on the specific isoforms of the tau protein. We set out to establish two series of aminoindole compounds connected by a carboxamide or triazine linker to evaluate the effectiveness of both families in decreasing the amount of misfolded α-syn and tau protein. Biophysical methods such as thioflavin T (ThT) fluorescence assays, photoinduced cross-linking of unmodified proteins (PICUP), and transmission electron microscopy (TEM) were deployed to assess the anti_x0002_aggregation potential of our aminoindole derivatives. M17D intracellular inclusion assay was used to detect the potency of our best compounds in reducing α-syn inclusions. We found that compounds A2, A8, and A17 from the amide series and compound T10 from the triazine series were effective in reducing the formation of α-syn and tau isoform 2N4R fibrils and oligomers in a dose-dependent manner. This was observed through the use of ThT fluorescence and PICUP assays and was validated with TEM. These same compounds reduced the development of α-syn inclusions in M17D neuroblastoma cells. Compounds A8 of the amide project and T10 of the triazine series were the most effective in preventing α-syn and tau isoform 2N4R aggregation. Compound T10 also showed reduction of ex vivo Aβ plaques and paired helical filaments (PHFs) in the brain tissue of a deceased AD patient showcasing its translational potential. These results demonstrate the potential of 4-aminoindole derivatives in preventing the aggregation α-syn and tau (2N4R isoform) proteins. The triazine derivatives series demonstrates the effectiveness of N_x0002_linked triazines in reducing misfolding of α-syn and tau in contrast to O-linked triazines and display the importance of symmetry in drug design.

Keywords: Alzheimer's disease ; Amide ; alpha-synuclein (synuclein alpha) ; fibril oligomer ; tau isoform 2n4r ; anti-aggregation compounds ; hyperphosphorylated protein tau ; paired helical filaments ; drug discovery ; triazine compound

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Product Details of [ 1122-58-3 ]

CAS No. :1122-58-3 MDL No. :MFCD00006418
Formula : C7H10N2 Boiling Point : -
Linear Structure Formula :C5NH4N(CH3)2 InChI Key :VHYFNPMBLIVWCW-UHFFFAOYSA-N
M.W : 122.17 Pubchem ID :14284
Synonyms :

Calculated chemistry of [ 1122-58-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.29
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 38.44
TPSA : 16.13 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.53
Log Po/w (XLOGP3) : 1.34
Log Po/w (WLOGP) : 1.15
Log Po/w (MLOGP) : 0.49
Log Po/w (SILICOS-IT) : 0.9
Consensus Log Po/w : 1.08

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.87
Solubility : 1.65 mg/ml ; 0.0135 mol/l
Class : Very soluble
Log S (Ali) : -1.28
Solubility : 6.4 mg/ml ; 0.0524 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.09
Solubility : 0.995 mg/ml ; 0.00815 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 1122-58-3 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P260-P262-P264-P270-P271-P273-P280-P301+P310+P330-P302+P352+P310-P304+P340+P311-P305+P351+P338+P310-P308+P311-P332+P313-P361+P364-P391-P403+P233-P405-P501 UN#:2811
Hazard Statements:H301+H331-H310-H315-H318-H370-H411 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1122-58-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 1122-58-3 ]
  • Downstream synthetic route of [ 1122-58-3 ]

[ 1122-58-3 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 1122-58-3 ]
  • [ 50533-97-6 ]
Reference: [1] New Journal of Chemistry, 2008, vol. 32, # 6, p. 1027 - 1037
  • 2
  • [ 75-44-5 ]
  • [ 1122-58-3 ]
  • [ 1193-24-4 ]
  • [ 1193-21-1 ]
Reference: [1] Patent: US5750694, 1998, A,
  • 3
  • [ 1122-58-3 ]
  • [ 84539-35-5 ]
Reference: [1] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1064 - 1069
[2] Tetrahedron Letters, 2006, vol. 47, # 49, p. 8693 - 8697
[3] Green Chemistry, 2018, vol. 20, # 19, p. 4448 - 4452
[4] Synthetic Communications, 2009, vol. 39, # 2, p. 215 - 219
[5] Tetrahedron Letters, 1997, vol. 38, # 25, p. 4415 - 4416
[6] Heterocycles, 1987, vol. 26, # 11, p. 2905 - 2910
[7] Chemical Communications, 2006, # 25, p. 2673 - 2674
[8] Journal of the American Chemical Society, 2017, vol. 139, # 7, p. 2557 - 2560
[9] Angewandte Chemie - International Edition, 2017, vol. 56, # 45, p. 14272 - 14276
[10] Tetrahedron Letters, 2008, vol. 49, # 1, p. 189 - 194
  • 4
  • [ 1122-58-3 ]
  • [ 84539-35-5 ]
  • [ 139111-73-2 ]
Reference: [1] Russian Journal of General Chemistry, 2009, vol. 79, # 5, p. 911 - 918
  • 5
  • [ 1122-58-3 ]
  • [ 109-97-7 ]
  • [ 100-36-7 ]
  • [ 5176-27-2 ]
Reference: [1] Patent: US5574017, 1996, A,
  • 6
  • [ 1122-58-3 ]
  • [ 163685-01-6 ]
  • [ 491-11-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1996, # 8, p. 1553 - 1558
  • 7
  • [ 1122-58-3 ]
  • [ 1801-10-1 ]
Reference: [1] Patent: US6441233, 2002, B1,
  • 8
  • [ 113399-37-4 ]
  • [ 1122-58-3 ]
  • [ 63710-33-8 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 4, p. 742 - 746[2] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 4, p. 821 - 825
[3] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 4, p. 742 - 746[4] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 4, p. 821 - 825
  • 9
  • [ 1122-58-3 ]
  • [ 4389-45-1 ]
  • [ 503-38-8 ]
  • [ 22223-49-0 ]
Reference: [1] Patent: US5962436, 1999, A,
  • 10
  • [ 1122-58-3 ]
  • [ 7417-18-7 ]
  • [ 124-63-0 ]
  • [ 121-44-8 ]
  • [ 36449-75-9 ]
Reference: [1] Patent: US6100293, 2000, A,
  • 11
  • [ 1122-58-3 ]
  • [ 5419-55-6 ]
  • [ 402-43-7 ]
  • [ 23287-26-5 ]
  • [ 145797-53-1 ]
  • [ 128796-39-4 ]
Reference: [1] Patent: US2003/109700, 2003, A1,
[2] Patent: US6197798, 2001, B1,
  • 12
  • [ 1122-58-3 ]
  • [ 84358-13-4 ]
Reference: [1] Patent: US6127422, 2000, A,
[2] Patent: EP806411, 1997, A2,
  • 13
  • [ 1122-58-3 ]
  • [ 3144-09-0 ]
  • [ 24424-99-5 ]
  • [ 121-44-8 ]
  • [ 147751-16-4 ]
Reference: [1] Patent: US6358981, 2002, B1, . Location in patent: Page column 22
  • 14
  • [ 1122-58-3 ]
  • [ 396092-82-3 ]
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 1, p. 238 - 241
[2] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3837 - 3849
[3] Tetrahedron Letters, 2010, vol. 51, # 50, p. 6622 - 6625
[4] Inorganic Chemistry, 2017, vol. 56, # 14, p. 8244 - 8256
[5] Patent: US2011/301148, 2011, A1, . Location in patent: Page/Page column 7
[6] Organic and Biomolecular Chemistry, 2013, vol. 11, # 46, p. 8073 - 8081
  • 15
  • [ 1122-58-3 ]
  • [ 24424-99-5 ]
  • [ 69684-69-1 ]
  • [ 255882-72-5 ]
YieldReaction ConditionsOperation in experiment
87% With triethylamine In dichloromethane To a solution of azetidine-2(S)-carboxylic acid, methyl ester hydrochloride salt (6.6 mmol, 1.0 g) in anhydrous dichloromethane (14 mL) was added di-tert-butyl dicarbonate (1.05 equiv; 6.9 mmol, 1.51 g), triethylamine (3.0 equiv; 19.8 mmol, 2.0 g, 2.76 mL), and 4-dimethyl-aminopyridine in that order at 25° C.
Evolution of gas was observed almost immediately and the reaction mixture became cloudy.
After stirring overnight (15 h) it was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated bicarbonate solution, and brine.
Drying (MgSO4), filtration, and concentration afforded N-(tert-butyloxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester as a pale yellow oil (1.24 g, 87percent yield) of satisfactory purity.
1H NMR (400 MHz, CDCl3): δ 4.63 (dd, 1H, J=9.2, 5.2 Hz), 4.05 (m, 1H), 3.89 (m, 1H), 3.79 (s, 3H), 2.51 (m, 1H), 2.18 (m, 1H), 1.43 (s, 9H).
Reference: [1] Patent: US6645939, 2003, B1,
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