Nuclear magnetic resonance and molecular modeling analysis of the interaction of the antimalarial drugs artelinic acid and artesunic acid with beta-cyclodextrin.
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 beta-cyclodextrin would result in complexes with increased aqueous solubility while retaining the potent antimalarial activity of these compounds. Preliminary complexation studies with natural beta-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 beta-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 beta-cyclodextrin via the primary face. NMR results indicate artesunic acid forms a similar complex with beta-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.
Hartell
Mark G
MG
Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910-7500, USA.
Hicks
Rickey
R
Bhattacharjee
Apurba K
AK
Koser
Brandon W
BW
Carvalho
Keith
K
Van Hamont
John E
JE
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D037621:Artemisinins / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology; D055672:Static Electricity; D013386:Succinates / Q000737:chemistry* / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000737:chemistry*
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D013386:Succinates; D047392:beta-Cyclodextrins; C062768:artelinic acid; C111789:artesunic acid; C031215:betadex