New 4-aminoquinoline Mannich base antimalarials. 1. Effect of an alkyl substituent in the 5'-position of the 4'-hydroxyanilino side chain.

@article{Raynes1999New4M,
  title={New 4-aminoquinoline Mannich base antimalarials. 1. Effect of an alkyl substituent in the 5'-position of the 4'-hydroxyanilino side chain.},
  author={Kaylene J. Raynes and Paul A. Stocks and Paul M. O’Neill and B. Kevin Park and Stephen A. Ward},
  journal={Journal of medicinal chemistry},
  year={1999},
  volume={42 15},
  pages={
          2747-51
        }
}
A new series of 4-aminoquinoline Mannich base derivatives have been synthesized, in which the 3'-diethylamino function of amodiaquine (AQ) is replaced by a 3'-tert-butylamino group and an aliphatic hydrocarbon entity is incorporated into the 5'-position of the 4'-hydroxyanilino side chain. Seven alkyl Mannich base derivatives were screened and found to be active against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. The propyl and isopropyl alkyl… 
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Three new derivatives of amodiaquine and amopyroquine were found to be active against both chloroquine‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM; one compound showed in vivo activity.
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TLDR
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References

SHOWING 1-10 OF 32 REFERENCES
Synthesis and antimalarial effects of 4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl] -6-alkylphenols and their N omega-oxides.
A series of 4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl]-6-alkylphenols and their N omega-oxides were synthesized by the condensation of 4,7-dichloroquinoline and 4,7-dichloroquinoline N…
The role of drug accumulation in 4-aminoquinoline antimalarial potency. The influence of structural substitution and physicochemical properties.
Synthesis, antimalarial activity, and molecular modeling of tebuquine analogues.
TLDR
A novel more efficient synthetic route to tebuquine analogues is developed which involves the use of a palladium-catalyzed Suzuki reaction to introduce the 4-chlorophenyl moiety into the4-hydroxyaniline side chain, which had the most favorable interaction energy in both the in vacuo and solvent-based simulation studies.
Synthesis, antimalarial activity, and quantitative structure-activity relationships of tebuquine and a series of related 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1'-biphenyl]-2-ols and N omega-oxides.
TLDR
Initial high activity against P. berghei infections in mice led to expanded studies that demonstrated in addition excellent activity against resistant strains of parasite, activity in primate models, and pharmacokinetic properties apparently allowing protection against infection for extended periods of time even after oral administration.
Amodiaquine as a prodrug: importance of metabolite(s) in the antimalarial effect of amodiaquine in humans.
Disposition of amopyroquin in rats and rabbits and in vitro activity against Plasmodium falciparum.
TLDR
The disposition of amopyroquin was studied in rats after a single 50-mg/kg oral dose and three metabolites were detected in both animal species (one was tentatively identified as the primary amine derivative), suggesting that the drug could be used through i.m. or oral administration.
The mechanism of bioactivation and antigen formation of amodiaquine in the rat.
A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum.
TLDR
There was a significant rank-order correlation between the IC50S of desethylamodiaquine and chloroquine, but not between amodiaquet and chlorquine, which suggests that the apparent cross-resistance betweenchloroquine and amodIAquine observed in clinical studies may be more closely related to the cross- Resistance between chloroquines and the metabolite rather than between chlorQuine and the parent compound.
Pharmacokinetic and pharmacodynamic study of amodiaquine and its two metabolites after a single oral dose in human volunteers.
TLDR
The inhibitory activity of patients' sera on Plasmodium falciparum growth in vitro appears to be directly related to the AQm1 concentration, and effective AQ concentrations should thus be analyzed in plasma rather than in whole blood.
Pharmacokinetics of intravenous amodiaquine.
TLDR
During intravenous injection there was a significant fall in systolic blood pressure in four subjects but there was no significant change in heart rate, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples.
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