Nuclear magnetic resonance and molecular modeling analysis of the interaction of the antimalarial drugs artelinic acid and artesunic acid with β-cyclodextrin

Mark G. Hartell, Rickey Hicks, Apurba K. Bhattacharjee, Brandon W. Koser, Keith Carvalho, John E. Van Hamont

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Abstract

The artemisinin derivatives artelinic acid and artesunic acid are members of a class of compounds that have shown promise for the treatment of multidrug resistant strains of Plasmodium falciparum. Unfortunately, these compounds exhibit poor solubility and stability in aqueous solution. The research presented herein was conducted to determine whether complexation of artelinic acid or artesunic acid with β-cyclodextrin would result in complexes with increased aqueous solubility while retaining the potent antimalarial activity of these compounds. Preliminary complexation studies with natural β-cyclodextrins were conducted as a proof of concept, with a primary focus on understanding the electrostatic interactions that stabilize the resulting complexes. Complex formation was monitored using UV spectroscopy. The structures of the resulting complexes were determined using multidimensional nuclear magnetic resonance spectroscopy (NMR) and molecular modeling. NMR results are most consistent for artelinic acid and β-cyclodextrin forming complexes in a ratio of 2:1; however, the presence of 1:1, 2:2, and 3:1 complexes in solution cannot be excluded based on the experimental data collected. The NMR data also indicate selective insertion of artelinic acid into the hydrophobic cavity of the β-cyclodextrin via the primary face. NMR results indicate artesunic acid forms a similar complex with β-cyclodextrin in a ratio of 1:1; again however, the presence of 1:1,2:2, and 3:1 complexes in solution cannot be ruled out.

Original languageEnglish (US)
Pages (from-to)2076-2089
Number of pages14
JournalJournal of Pharmaceutical Sciences
Volume93
Issue number8
DOIs
StatePublished - Jan 1 2004

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Keywords

  • Artelinic acid
  • Molecular modeling
  • NMR
  • β-cyclodextrin

ASJC Scopus subject areas

  • Pharmaceutical Science

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