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[ CAS No. 74-11-3 ] {[proInfo.proName]}

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Chemical Structure| 74-11-3
Chemical Structure| 74-11-3
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Product Citations

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_x005f_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_x005f_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_x005f_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 [ 74-11-3 ]

CAS No. :74-11-3 MDL No. :MFCD00002531
Formula : C7H5ClO2 Boiling Point : -
Linear Structure Formula :C6H4Cl(COOH) InChI Key :XRHGYUZYPHTUJZ-UHFFFAOYSA-N
M.W : 156.57 Pubchem ID :6318
Synonyms :

Calculated chemistry of [ 74-11-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.41
TPSA : 37.3 ?2

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) : -5.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.44
Log Po/w (XLOGP3) : 2.65
Log Po/w (WLOGP) : 2.04
Log Po/w (MLOGP) : 2.2
Log Po/w (SILICOS-IT) : 1.86
Consensus Log Po/w : 2.04

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.86
Solubility : 0.217 mg/ml ; 0.00139 mol/l
Class : Soluble
Log S (Ali) : -3.08
Solubility : 0.129 mg/ml ; 0.000823 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.37
Solubility : 0.663 mg/ml ; 0.00424 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 74-11-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 74-11-3 ]

* 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.

  • Downstream synthetic route of [ 74-11-3 ]

[ 74-11-3 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 74-11-3 ]
  • [ 108-95-2 ]
  • [ 42019-78-3 ]
  • 2
  • [ 74-11-3 ]
  • [ 42860-10-6 ]
  • 3
  • [ 7790-94-5 ]
  • [ 7726-95-6 ]
  • [ 74-11-3 ]
  • [ 42860-10-6 ]
  • 4
  • [ 74-11-3 ]
  • sodium bromide [ No CAS ]
  • sulfur [ No CAS ]
  • [ 42860-10-6 ]
  • 6
  • (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine [ No CAS ]
  • [ 17794-48-8 ]
  • [ 56602-33-6 ]
  • [ 7087-68-5 ]
  • [ 74-11-3 ]
  • [ 445478-99-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; trifluoroacetic acid; In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; (27c) 4-Chlorobenzoic acid (258 mg) was dissolved in DMF (8 mL) prior to the addition of Hunig's base (1.0 mL). After cooling to 0 C., BOP Reagent (729 mg) was added. This was stirred for 15 min before (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b), (300 mg) was added as a DMF solution (2 mL). The resulting mixture warmed to rt and was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. The resulting material was dissolved in CH2Cl2 (10 mL) and cooled to 0 C. TFA (1.2 mL) was added and the reaction was stirred for 2 h. This solution was concentrated prior to the addition of DMF (8 mL). After cooling to 0 C., Hunig's base (1 mL) and <strong>[17794-48-8][[3-(trifluoromethyl)benzoyl]amino]acetic acid</strong> (386 mg) were added. BOP Reagent (655 mg) was added next, and the mixture was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. This was stirred in 1:1 EtOAc/hexane and then filtered to give the title benzamide N-[2-[[(1S,2R)-2-[(4-chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide (310 mg) as a solid. MS found: (M+H)+=468.2.
  • 8
  • [ 57297-29-7 ]
  • [ 74-11-3 ]
  • C11H11ClN2O [ No CAS ]
  • 9
  • [ 138588-22-4 ]
  • [ 74-11-3 ]
  • 4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; 3-Pyridm-2-yl-[l,2,4]thiadiazol-5-yIamine (50 mg, 0.28 mmol) and p-chlorobenzoic acid (44 mg, 0.28 mmol) were mixed in 1 mL of anhydrous dimethvlformamide, to which solution was added N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) followed by addition of 1 - [his(dimethylammo)methylene]~ 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (1 14 mg, 0.30 mmol). The mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to obtain Compound 7 as a white solid (53.5 mg, 60%). NMR (400 MHz, DMSO-rfe) delta ppm 7.36 - 7.64 (m, 1 H) 7.69 (d, J=8.69 Hz, 2 H) 7.91 - 8.10 (m, 1 H) 8.12 - 8.34 (m, 3 H) 8.72 (d, J=4.00 Hz, 1 H); LCMS (M/Z): M+HT' 317.
  • 10
  • [ 392331-66-7 ]
  • [ 74-11-3 ]
  • tert-butyl 4-((4-chlorobenzamido)methyl)-4-hydroxypiperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; for 2h; A solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine- 1 -carboxylate (0.25 g, 1.086 mmol) and 4-chlorobenzoic acid (0.204 g, 1.303 mmol) in DMF (2 mL)was treated with triethylamine (0.454 mL, 3.26 mmol) followed by BOP (0.576 g, 1.303 mmol). The reaction was stirred for 2h then quenched with dil. aq. HOAc. This resulted in the formation of a precipitate, so the mixture was filtered and rinsed with water. It was then suspended in dil. aq. sodium bicarbonate, sonicated, then filtered, rinsed with water, and air-dried to afford tert-butyl 4-((4-chlorobenzamido)methyl)-4-hydroxypiperidine- 1-carboxylate (0.38 g, 90% yield) as a colorless solid, mp 172-173 C. MS(ES): m/z = 369 [M+H]. tR = 0.93 mm (Method A).
  • 11
  • [ 35418-07-6 ]
  • [ 74-11-3 ]
  • C17H16ClNO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid.
  • 13
  • [ 3325-11-9 ]
  • [ 74-11-3 ]
  • 1-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-chlorophenyl)urea [ No CAS ]
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