Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity.

doi:10.1021/JM990437L

Paper

Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity.

Published Jan 27, 2000 · T. Egan, R. Hunter, C. Kaschula

Journal of medicinal chemistry

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292

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3

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Abstract

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.

In Vitro Study

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Study Snapshot

Chloroquine and related antimalarials act by complexing Fe(III)PPIX, inhibiting beta-hematin formation, and requiring a basic amino side chain for drug accumulation in parasite food vacuoles.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity.

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References

Citations

Aromaticity as a Useful Descriptor of Pharmacological Activity: A Case Study of Quinoline-Based Antimalarial Agents

Aromaticity is a key factor in determining the antimalarial activity of quinoline-based compounds, with pyridine-type rings being more important for drug activity.

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants

LDT-623 shows promising multistage antimalarial activity and lacks cross-resistance with PfCRT and PfMDR1 mutants, potentially addressing artemisinin resistance in malaria treatment.

Synthesis and Anti-Trypanosoma cruzi Activity of New Pyrazole-Thiadiazole Scaffolds

New pyrazole-thiadiazole compounds show promising antiparasitic activity against Trypanosoma cruzi, with potential for oral delivery and favorable physicochemical parameters.

Organometallic analogs of chloroquine: Challenges and perspectives as anti‐malarial agents

Organometallic analogs of chloroquine show potential as novel, non-toxic antimalarial agents due to resistance against current drugs.

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies.

The novel hybrid drug series, combining quinoline, chloroquine, pamaquine, and primaquine, shows promising antimalarial activity against Plasmodium falciparum, with compound 1b being the most effective against drug-resistant strains.