Syntheses in the Quinoline Series. III. The Nitration of 2-Chloro-4-methylquinoline and the Preparation of Some 2-Hydroxy-4-methyl-8-(dialkylaminoalkyl)-aminoquinolines

Johnson, Oscar H.; Hamilton, Cliff S.

doi:10.1021/ja01856a003

Cited by 6 publications

(4 citation statements)

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“…Compound 5 General procedure for the preparation of 4-methyl-8-nitroquinolin-2(1H)-one 7 34 , quinolin-2(1H)-one 14 35 , 5-nitroquinolin-2(1H)-one 19 16 and 8-nitroquinolin-2(1H)-one 20 16 .…”

Section: Acknowledgmentsmentioning

confidence: 99%

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Pedron

Boudot

Hutter

et al. 2018

European Journal of Medicinal Chemistry

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To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.

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Section: Acknowledgmentsmentioning

confidence: 99%

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Pedron

Boudot

Hutter

et al. 2018

European Journal of Medicinal Chemistry

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“…None of the compounds lacking the western para substituent (e.g., 23-25) displayed impressive affinity, whereas p-methyl (14), p-methoxy (21), and p-chloro (26) exhibited high affinity. Increasing the size of the para substituent to isopropoxy (27) or isopentoxy (28) resulted in decreased affinity, suggesting that these para substituents are larger than optimal. No clear correlation between the electronic properties of the para substituent and affinity was observed.…”

Section: Resultsmentioning

confidence: 99%

“…However, for the exploration of the eastern part, this protocol represents a four-step sequence for each compound. Thus, an alternative approach was developed using 2-chloro-6-nitroquinoline 11 as the starting point (Scheme ) . Reduction of the nitro group by tin(II) chloride or by platinum-catalyzed hydrogenation afforded 6-amino-2-chloroquinoline 12 .…”

Section: Chemistrymentioning

confidence: 99%

“…Thus, an alternative approach was developed using 2-chloro-6-nitroquinoline 11 as the starting point (Scheme 4). 28 Reduction of the nitro group by tin(II) chloride or by platinum-catalyzed hydrogenation afforded 6-amino-2-chloroquinoline 12. Treatment of 12 with the appropriate acid chloride afforded the intermediates 13, which were converted to target compounds 5 upon heating with the appropriate amine.…”

Section: Chemistrymentioning

confidence: 99%

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6-Acylamino-2-aminoquinolines as Potent Melanin-Concentrating Hormone 1 Receptor Antagonists. Identification, Structure−Activity Relationship, and Investigation of Binding Mode

Ulven¹,

Frimurer²,

Receveur³

et al. 2005

J. Med. Chem.

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Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.

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Synthesis of the Quinoline Ring System

Jones¹

1977

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Syntheses in the Quinoline Series. III. The Nitration of 2-Chloro-4-methylquinoline and the Preparation of Some 2-Hydroxy-4-methyl-8-(dialkylaminoalkyl)-aminoquinolines

Abstract: 2-MeTHOXY-4-METHYL-S-AMINO(JUINOLINE 2867 4. 4-Vinylquinoline, lepidine and pyridine 5. Several new quinoline compounds were prewere found to react with maleic anhydride with pared from 2-hydroxy-4-(bromomethyl)-quinoline, evolution of carbon dioxide.

Cited by 6 publications

References 0 publications

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

6-Acylamino-2-aminoquinolines as Potent Melanin-Concentrating Hormone 1 Receptor Antagonists. Identification, Structure−Activity Relationship, and Investigation of Binding Mode

Synthesis of the Quinoline Ring System

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