Intramolecular Hydrogen Bonding in 7-Chloro-4-diethylaminoethylaminoquinoline

Compounds of pharmacological interest containing a 4-amino-2-alkyl-1,2,3,4-tetrahydroquinoline core structure were prepared starting from 4-chloroquinoline. This has been executed both in solution with a 1-benzyl-4-chloroquinolinium salt and on a solid support with a 1-(4-benzyloxybenzyl-PS)-4-chloroquinolinium resin as key intermediates. Diversification of such intermediates was accomplished through N-arylation of position 4 and subsequent nucleophilic addition of Grignard reagents of position 2 to deliver the expected 4-amino-2-alkyl-1,2,3,4-tetrahydroquinolines in 20-60% yields. The methods described within clearly demonstrate that the quinolinium salts are very efficient intermediates for parallel synthesis.

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Structure−Function Relationships in Aminoquinolines: Effect of Amino and Chloro Groups on Quinoline−Hematin Complex Formation, Inhibition of β-Hematin Formation, and Antiplasmodial Activity

Egan

et al. 1999

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Comparison of 19 aminoquinolines supports the hypothesis that chloroquine and related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)PPIX), inhibiting its conversion to beta-hematin (hemozoin) and hence its detoxification. The study suggests that a basic amino side chain is also essential for antiplasmodial activity. 2- And 4-aminoquinolines are unique in their strong affinity for Fe(III)PPIX, and attachment of side chains to the amino group has relatively little influence on the strength of complex formation. Association with Fe(III)PPIX is necessary, but not sufficient, for inhibiting beta-hematin formation. Presence of a 7-chloro group in the 4-aminoquinoline ring is a requirement for beta-hematin inhibitory activity, and this is also unaffected by side chains attached to the amino group. In turn, beta-hematin inhibitory activity is necessary, but not sufficient, for antiplasmodial activity as the presence of an aminoalkyl group attached to the 4-amino-7-chloroquinoline template is essential for strong activity. We thus propose that the 4-aminoquinoline nucleus of chloroquine and related antimalarials is responsible for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of beta-hematin formation, and the basic amino side chain is required for drug accumulation in the food vacuole of the parasite.

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Intramolecular Hydrogen Bonding in 7-Chloro-4-diethylaminoethylaminoquinoline

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Spezielle Anwendungsgebiete

Spezielle Anwendungsgebiete

Use of Quinolinium Salts in Parallel Synthesis for the Preparation of 4-Amino-2-alkyl-1,2,3,4-tetrahydroquinoline

Structure−Function Relationships in Aminoquinolines: Effect of Amino and Chloro Groups on Quinoline−Hematin Complex Formation, Inhibition of β-Hematin Formation, and Antiplasmodial Activity

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