1198-40-9

Usage

Uses

Used in Pharmaceutical Industry:
7-Chloro-4-quinolinamine is used as an active pharmaceutical ingredient for its ability to inhibit the conversion of ferriprotoporphyrin IX (Fe(III)PPIX) to β-hematin (hemozoin). This property is particularly useful in the development of drugs targeting diseases caused by protozoan parasites, such as malaria, where the inhibition of hemozoin formation is a key strategy to disrupt the parasite's survival mechanism.
Additionally, due to its interaction with ferriprotoporphyrin IX, 7-chloro-4-quinolinamine may also have potential applications in other therapeutic areas where the modulation of Fe(III)PPIX conversion is beneficial. Further research and development are required to explore these possibilities and optimize the compound's efficacy and safety profile for various medical applications.

Synthesis Reference(s)

Journal of the American Chemical Society, 69, p. 704, 1947 DOI: 10.1021/ja01195a501

Synthesis

4-amino-7-chloroquinoline is obtained byreacting 7-chloro-4-hydrazinoquinoline ,sodium borohydride with nickel (II) chloride hexahydrate in methanol.To a suspension of 7-chloro-4-hydrazinoquinoline (1.67 g, 8.6 mmol) and nickel (II) chloride hexahydrate (2.00 g, 8.6 mmol) in methanol (33 ml), sodium borohydride (0.98 g, 25.8 mmol) was added cautiously while stirring the reaction mixture vigorously at room temperature and left to react overnight. The reaction mixture was filtered through celite pad. Water was used to dilute the filtrate layer and then washed with ethyl acetate. The organic layer was dried with magnesium sulphate and concentrated in vacuo to give the title compound as a yellow powder (1.09 g, 72%): mp: 143 – 147 ℃ (Lit.: 147 – 148 ℃) ;vmax/cm-1 3337 s (N-H), 1642 m (C=N), 1609 m and 1575 m (C=N); δH (300 MHz; DMSO-d6) 8.28 (1H, d, J 5.3, C(2)H), 8.19 (1H, d, J 9.1, C(5)H), 7.76 (1H, d, J 1.6, C(8)H), 7.39 (1H, dd, J 9.1, 1.6, C(6)H), 7.03 (2H, s, NH2), 6.57 (1H, d, J 5.3, C(3)H); δC (75 MHz; DMSO-d6) 152.0 (Ar-C), 151.1 (C(2)H), 148.9 (Ar-C), 133.7 (Ar-C), 126.8 (C(8)H), 124.8 (C(5)H), 123.9 (C(6)H), 117.0 (Ar-C), 102.7 (C(3)H); m/z (-ES) 179 (100%, [M+H]- with 35Cl), 181 (35%, [M+H]- with 37Cl); found by +ES 179.0377, C9H8ClN2 ([M+H]+ with 35Cl), requires 179.0371, error 3.3 ppm.

InChI:InChI=1/C9H7ClN2/c10-6-1-2-7-8(11)3-4-12-9(7)5-6/h1-5H,(H2,11,12)

Upstream product

• 86-98-6 4,7-dichloroquinoline 
• 100-63-0 phenylhydrazine 
• 26707-52-8 7-chloro-4-methoxyquinoline 
• 631-61-8 ammonium acetate 
• 69063-03-2 4-azido-7-chloro-quinoline 
• 75-64-9 tert-butylamine 
• 109-73-9 N-butylamine 
• 108-00-9 N,N-dimethylethylenediamine 
• 23834-14-2 7-chloro-4-hydrazinoquinoline 
• 110-85-0 piperazine 
• 109-83-1 (2-hydroxyethyl)(methyl)amine 
• 98591-57-2 7-chloro-4-iodoquinoline 
• 100-36-7 N,N-diethylethylenediamine 
• 75-31-0 isopropylamine 

Downstream Products

• 100671-88-3 4--7-chloroquinoline 
• 100671-93-0 7-chloro-4-quinoline 
• 100671-94-1 4--7-chloroquinoline 
• 100671-90-7 4--7-chloroquinoline 
• 100672-00-2 7-chloro-4-quinoline 
• 100671-89-4 4--7-chloroquinoline 
• 100671-95-2 4--7-chloroquinoline 
• 100671-96-3 [4-(7-Chloro-quinolin-4-ylcarbamoyl)-phenyl]-carbamic acid ethyl ester 
• 100671-97-4 [4-(7-Chloro-quinolin-4-ylcarbamoyl)-phenyl]-carbamic acid isobutyl ester 
• 100671-98-5 4-N-<4-(N,N'-dicarbomethoxyguanidinobenzoyl)>amino-7-chloroquinoline 
• 100671-99-6 C₂₃H₂₂ClN₅O₅ 
• 1104050-93-2 (+/-)-7-chloro-N-{(4-chlorophenyl)[4-(pyrrolidin-1-ylmethyl)phenyl]phenylmethyl}-4-aminoquinoline 
• 1050527-00-8 (+/-)-7-chloro-N-{(4-chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-4-aminoquinoline 
• 1370000-35-3 4-amino-7-chloro-1-(5-(1,3-dioxoisoindolin-2-yl)pentan-2-yl)quinolinium bromide 

Relevant academic research and scientific papers

Synthesis, in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides

A series of 4-aminoquinolinyl-chalcone amides 11-19 were synthesized through condensation of carboxylic acid-functionalized chalcone with aminoquinolines, using 1,1′-carbonyldiimidazole as coupling agent These compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (W2) strains of Plasmodium falciparum Their cytotoxicity towards the WI-38 cell line of normal human fetal lung fibroblast was determined All compounds were found active, with IC50 values ranging between 0.04-0.5 μM and 0.07-1.8 μM against 3D7 and W2, respectively They demonstrated moderate to high selective activity towards the parasitic cells in the presence of mammalian cells However, amide 15, featuring the 1,6-diaminohexane linker, despite possessing predicted unfavourable aqueous solubility and absorption properties, was the most active of all the amides tested It was found to be as potent as CQ against 3D7, while it displayed a two-fold higher activity than CQ against the W2 strain, with good selective antimalarial activity (SI = 435) towards the parasitic cells During this study, amide 15 was thus identified as the best drug-candidate to for further investigation as a potential drug in search for new, safe and effective antimalarial drugs

Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase

Eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7)were synthesised and tested as inhibitors of human acetylcholinesterase (AChE)and butyrylcholinesterase (BChE). Both enzymes were inhibited by all of the compounds with inhibition constants (Ki)ranging from 0.50 to 50 μM exhibiting slight selectivity toward AChE over BChE. The most potent inhibitors of AChE were compounds with an n-octylamino chain or adamantyl group. The shortening of the chain length resulted in a decrease in AChE inhibition by 5–20 times. Docking studies revealed that the quinoline group within the AChE active site was positioned in the choline binding site, while the C(4)-amino group substituents, depending on their lipophilicity, could establish hydrogen bonds or π-interactions with residues of the peripheral anionic site. The most potent inhibitors of BChE were compounds with the most voluminous substituent on C(4)-amino group (adamantyl)or those with a stronger electron withdrawing substituent on C(7)(trifluormethyl group). Based on AChE inhibition, compounds with an n-octylamino chain or adamantyl substituent were shown to possess the capacity for further development as potential drugs for treatment of neurodegenerative diseases.

Antimalarial activity of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives

Chloroquine (CQ) has been used as first line malaria therapeutic drug for decades. Emergence of CQ drug-resistant Plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. Mefloquine (MQ) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage P. falciparum (Pf). However, serious CNS toxicity of MQ has compromised its clinical value as a prophylaxis drug. Therefore, new and inexpensive antimalarial drugs with no cross-resistance to CQ or CNS toxicity are urgently needed to combat this deadly human disease. In this study, a series of new 4-amidinoquinoline (4-AMQ) and 10-amidinobenzonaphthyridine (10-AMB) derivatives were designed, prepared, and assessed to search for new therapeutic agents to replace CQ and MQ. The new derivatives displayed high activity in vitro and in vivo, with no cross-resistance to CQ, and none were toxic in mice up to 160 mpk × 3. The best compound shows IC50 + channel blockage testing, negativity in the Ames test, and 5/5 cure @ 1/2 of 50 h in mice, which made it a good MQ replacement candidate.

Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth

Considerable data now support the hypothesis that chloroquine (CQ)- hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin μ-oxo dimers in a cofacial π-π sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 105 M-1 compared to 4.0 x 105 M-1 for CQ. Remarkably, we were not able to measure any significant interaction between hematin μ-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin μ-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable π-π interaction observed in the CQ-hematin μ-oxo dimer complex derives from a favorable alignment of the out-of-plane π-electron density in CQ and hematin μ-oxo dimer at the points of intermolecular contact. For 4- aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC50 values suggests that other properties of the CQ-hematin μ-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin μ-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.

SMALL MOLECULE INHIBITORS OF AUTOPHAGY AND HISTONE DEACTYLASES AND USES THEREOF

This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinoline or thioxanthenone (or similar) structure which function as autophagy inhibitors and/or histone deactylase inhibitors, and their use as therapeutics for the treatment of conditions characterized with aberrant autophagy activity and/or aberrant HDAC activity (e.g., cancer, pulmonary hypertension, diabetes, neurodegenerative disorders, aging, heart disease, rheumatoid arthritis, infectious diseases, conditions and symptoms caused by a viral infection (e.g., COVID-19)).

Novel Aminoquinoline Derivatives Significantly Reduce Parasite Load in Leishmania infantum Infected Mice

In this Letter, a detailed analysis of 30 4-aminoquinoline-based compounds with regard to their potential as antileishmanial drugs has been carried out. Ten compounds demonstrated IC50 50 1 μM against intramacrophage L. infantum amastigotes. Two compounds showed dose-dependent enhancement of NO and ROS production by bone marrow-derived macrophages and remarkable reduction of parasite load in vivo, with advantage of being short-term and orally active. To the best of our knowledge, this is the first example of 4-amino-7-chloroquinoline derivatives active in Leishmania infantum infected mice.

New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model

The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.

Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species

The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NHAryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds.

In situ generation of ammonia for the copper-catalyzed synthesis of primary aminoquinolines

The synthesis of primary aminoquinolines from iodoquinolines was carried out in the presence of copper(i) iodide and formamide as the solvent and source of ammonia generated in situ. The reaction proceeded under mild conditions within a few hours and was applicable to various iodoquinolines.

Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species

The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NH-Aryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds.