Bistacrine derivatives as new potent antimalarials.
Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure-activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50 values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Ines
I
Schmidt
Institute of Molecular Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany.
Gabriele
G
Pradel
Institute of Molecular Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany.
Ludmilla
L
Sologub
Institute of Molecular Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany.
Alexandra
A
Golzmann
Institute of Molecular Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany.
Che J
CJ
Ngwa
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Anna
A
Kucharski
Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany.
Tanja
T
Schirmeister
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address: ulrike.holzgrabe@uni-wuerzburg.de.
Ulrike
U
Holzgrabe
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D019281:Dimerization; D020128:Inhibitory Concentration 50; D010961:Plasmodium / Q000187:drug effects; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D013619:Tacrine
Antimalarials; Bistacrines; Falcipain-2 inhibitors