Synthesis and Antimalarial Activity of Novel Dihydro-Artemisinin Derivatives

The Plasmodium falciparum cysteine protease falcipain-2, one of the most promising targets for antimalarial drug design, plays a key role in parasite survival as a major peptide hydrolase within the hemoglobin degradation pathway. In this work, a series of novel dihydroartemisinin derivatives based on (thio)semicarbazone scaffold were designed and synthesized as potential falcipain-2 inhibitors. The in vitro biological assay indicated that most of the target compounds showed excellent inhibition activity against P. falciparum falcipain-2, with IC50 values in the 0.29–10.63 μM range. Molecular docking studies were performed to investigate the binding affinities and interaction modes for the inhibitors. The preliminary SARs were summarized and could serve as a foundation for further investigation in the development of antimalarial drugs.

• Publication year

  2011

• Venue

  Molecules

• Publication date

  2011-05-30

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3390/molecules16064527PMID 21629181PMCID 6264262
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Preliminary structure-activity relationships were summarized to support further antimalarial drug design.

  Confidence 0.86

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• Molecular docking was used to examine binding affinities and interaction modes of the inhibitors against falcipain-2.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• Most of the synthesized compounds inhibited P. falciparum falcipain-2 in vitro, with IC50 values ranging from 0.29 to 10.63 μM.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• Novel dihydroartemisinin derivatives built on a (thio)semicarbazone scaffold were designed and synthesized as candidate falcipain-2 inhibitors.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review

• antimalarial drug design

  research goal, drug design

  The medicinal chemistry goal of developing compounds that can act against malaria-causing parasites.

  Aliases: antimalarial design

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• dihydroartemisinin derivatives

  compound, chemical series

  Synthetic chemical compounds derived from dihydroartemisinin that were prepared and evaluated in this work.

  Aliases: DHA derivatives

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• falcipain-2

  target, enzyme

  A Plasmodium falciparum cysteine protease involved in hemoglobin degradation and used here as the molecular target.

  Aliases: pf falcipain-2

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• in vitro biological assay

  assay, measurement

  A laboratory assay used to measure the inhibitory activity of the compounds against falcipain-2.

  Aliases: bioassay, in vitro assay

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• molecular docking

  method, computational method

  A computational modeling approach used to estimate how the inhibitors fit and interact with falcipain-2.

  Aliases: docking

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• plasmodium falciparum

  organism, parasite

  The malaria parasite species from which falcipain-2 is described in the abstract.

  Aliases: P. falciparum

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• structure-activity relationships

  analysis, medicinal chemistry concept

  Observed links between the compounds' chemical structures and their measured biological activities.

  Aliases: SARs

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review
• (thio)semicarbazone scaffold

  chemical scaffold, structure

  The semicarbazone or thiosemicarbazone chemical framework attached to the dihydroartemisinin derivatives.

  Aliases: thiosemicarbazone scaffold, semicarbazone scaffold

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) review

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