- Synthesis, in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides
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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
- Smit, Frans J.,N'Da, David D.
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- Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase
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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.
- Bosak, Anita,Opsenica, Dejan M.,?inko, Goran,Zlatar, Matija,Kovarik, Zrinka
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- Antimalarial activity of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives
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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.
- Korotchenko, Vasiliy,Sathunuru, Ramadas,Gerena, Lucia,Caridha, Diana,Li, Qigui,Kreishman-Deitrick, Mara,Smith, Philip L.,Lin, Ai J.
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- Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth
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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.
- Vippagunta, Sudha Rani,Dorn, Arnulf,Matile, Hugues,Bhattacharjee, Apurba K.,Karle, Jean M.,Ellis, William Y.,Ridley, Robert G.,Vennerstrom, Jonathan L.
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- SMALL MOLECULE INHIBITORS OF AUTOPHAGY AND HISTONE DEACTYLASES AND USES THEREOF
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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)).
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Page/Page column 43-44
(2021/05/07)
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- Novel Aminoquinoline Derivatives Significantly Reduce Parasite Load in Leishmania infantum Infected Mice
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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.
- Konstantinovi?, Jelena,Videnovi?, Milica,Orsini, Stefania,Bogojevi?, Katarina,D'Alessandro, Sarah,Scaccabarozzi, Diletta,Terzi? Jovanovi?, Nata?a,Gradoni, Luigi,Basilico, Nicoletta,?olaja, Bogdan A.
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supporting information
p. 629 - 634
(2018/05/15)
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- New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model
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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.
- Konstantinovi?, Jelena,Kiris, Erkan,Kota, Krishna P.,Kugelman-Tonos, Johanny,Videnovi?, Milica,Cazares, Lisa H.,Terzi? Jovanovi?, Nata?a,Verbi?, Tatjana ?.,Andjelkovi?, Boban,Duplantier, Allen J.,Bavari, Sina,?olaja, Bogdan A.
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supporting information
p. 1595 - 1608
(2018/03/06)
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- Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species
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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.
- Nguyen, Thuy,Yang, Tianming,Go, Mei-Lin
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p. 1830 - 1838
(2015/03/14)
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- In situ generation of ammonia for the copper-catalyzed synthesis of primary aminoquinolines
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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.
- Aillerie, Alexandre,Pellegrini, Sylvain,Bousquet, Till,Pélinski, Lydie
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p. 1389 - 1391
(2014/05/06)
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- Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species
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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.
- Nguyen, Thuy,Yang, Tianming,Go, Mei-Lin
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supporting information
p. 1830 - 1838
(2014/04/17)
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- Structure-activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods
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In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of β-hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R = Me) and ethylamine (R = EtNH2) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, log K values for the simple 4-aminoquinoline series (R = H) were found to correlate with the hydrophobicity constant (π) of the group X. The log K values for the series with R = Me and EtNH2 were found to correlate with those of the series with R = H. The log of the 50% β-hematin inhibitory activity (log BHIA50) was found to correlate with log K and either meta (σm) or para (σp) Hammett constants for the series with R = Me and EtNH2, but not the simple series with R = H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that log K values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while log BHIA50 values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of β-hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible.
- Nsumiwa, Samkele,Kuter, David,Wittlin, Sergio,Chibale, Kelly,Egan, Timothy J.
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supporting information
p. 3738 - 3748
(2013/07/19)
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- METHOD OF SYNTHESIS OF FERROQUINE BY CONVERGENT REDUCTIVE AMINATION
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The invention relates to a method of synthesis of ferroquine of formula (F) or of its metabolite of formula (Fm): comprising a reaction of reductive amination, said reaction comprising: (i) a stage of condensation of an aldehyde-amino ferrocene of formula (III), in which R represents a hydrogen atom or a methyl group, with 7-chloroquinolin-4-amine as shown below, followed by (ii) a stage of reduction of the product of condensation obtained in the preceding stage and (iii) then a stage of hydrolysis of the reaction mixture in the presence of an aqueous solution of ammonia or of citric acid.
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Paragraph 0997; 0098
(2013/04/24)
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- Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials
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A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain-inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites.
- Perez, Bianca C.,Teixeira, Catia,Figueiras, Marta,Gut, Jiri,Rosenthal, Philip J.,Gomes, Jose R.B.,Gomes, Paula
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supporting information; experimental part
p. 887 - 899
(2012/09/10)
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- AMINOQUINOLINIUM SALTS, METHODS OF THEIR PRODUCTION AND THEIR USE AS ACTIVE AGENTS FOR BIOTECHNOLOGICAL AND MEDICAL APPLICATIONS AGAINST BINARY TOXINS
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The present invention relates to aminoquinoline salts, their uses and to methods of synthesizing such aminoquinoline salts. Moreover, the present invention relates to compositions comprising aminoquinoline salts in accordance with the present invention. The present invention relates to bioactive compounds from the class of aminoquinoline compounds, and in particular their inhibitory effects on the binary toxins of an AB-type of a number of bacteria, such as Clostridium perfringens, Clostridium botulinum, and Bacillus anthracis. The invention also relates to the use of these aminoquinoline compounds as drugs, more particularly as drugs for the treatment of bacterial infections, even more particularly bacterial infections caused by bacteria which produce pore forming toxins of a binary type. The present invention also relates to methods of producing the compounds in accordance with the present invention.
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(2012/04/17)
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- METHOD OF SYNTHESIS OF FERROQUINE BY CONVERGENT REDUCTIVE AMINATION
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The invention relates to a method of synthesis of ferroquine of formula (F) or of its metabolite of formula (Fm): comprising a reaction of reductive amination, said reaction comprising: (i) a stage of condensation of the aldhehyde-amino ferrocene of formula (1 ), which R represents a hydrogen atom or a methyl group, with the 7-chloroquinolin- amine of formula (2) as shown below, followed by (ii) a stage of reduction of the product of condensation obtained in the preceding stage (iii) then a stage of hydrolysis of the reaction mixture in the presence of an aqueous solution of ammonia or of citric acid.
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(2012/01/05)
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- Synthesis and in vitro antitubercular activity of a series of quinoline derivatives
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A series of 33 quinoline derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Compounds 5e and 5f exhibited a significant activity at 6.25 and 3.12 μg/mL, respectively, when compared with first line drugs such as ethambutol and could be a good starting point to develop new lead compounds in the fight against multi-drug resistant tuberculosis.
- de Souza, Marcus V.N.,Pais, Karla C.,Kaiser, Carlos R.,Peralta, Monica A.,de L. Ferreira, Marcelle,Lourenco, Maria C.S.
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experimental part
p. 1474 - 1480
(2009/08/15)
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- Microwave-assisted synthesis of 4-quinolylhydrazines followed by nickel boride reduction: a convenient approach to 4-aminoquinolines and derivatives
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Nickel(II) chloride/sodium borohydride combination was employed for the reduction of 4-hydrazinoquinoline derivatives to the corresponding anilines. This reductive protocol was efficiently applied for the reductive cleavage of monosubstituted hydrazines. We described herein the microwave-assisted synthesis of 4-hydrazinoquinolines, which furnished a high yielding and rapid two-step procedure for the synthesis, under mild conditions, of 4-aminoquinolines as antimalarial precursors.
- Gemma, Sandra,Kukreja, Gagan,Tripaldi, Pierangela,Altarelli, Maria,Bernetti, Matteo,Franceschini, Silvia,Savini, Luisa,Campiani, Giuseppe,Fattorusso, Caterina,Butini, Stefania
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p. 2074 - 2077
(2008/09/18)
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- N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation and their use as antimalarials
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Disclosed are N,N'-bis(quinolin-4-yl)diamine derivatives of general formula I wherein R1 signifies halogen or trifluoromethyl, R2 signifies hydrogen or halogen, A signifies cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 and phenylene-1,2; n is 1 or 2; m is 1 or 2, as well as their pharmaceutically acceptable salts. These products are useful as agents for preventing malaria and for treating it, especially where the pathogens are resistant to chloroquine. STR1
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- Photolysis of Quinolyl and Isoquinolyl Azides in Primary and Secondary Aliphatic Amines: Synthesis of Bicyclic Azepines, Diazepines, and Quinolyl- and Isoquinolyl-diamines
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Photolysis of the title compounds in primary aliphatic amines gave in some cases bicyclic azepines and diazepines as well as o-diamines, while in secondary amines mainly the appropriate o-diamines are obtained.On the basis of the many examples studied guidelines are put forward to predict the nature of products from photolysis of bicyclic azides in primary and secondary amines and to obtain maximum yields.
- Hollywood, Frank,Nay, Barry,Scriven, Eric F. V.,Suschitzky, Hans,Khan, Zafar U.,Hull, Roy
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p. 421 - 429
(2007/10/02)
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