Development of piperazine-tethered heterodimers as potent antimalarials against chloroquine-resistant P. falciparum strains. Synthesis and molecular modeling.
The design, synthesis, and antiplasmodial activity of antimalarial heterodimers based on the 1,4-bis(3-aminopropyl)piperazine linker is reported. In this series key structural elements derived from quinoline antimalarials were coupled to fragments capable of coordinating metal ions. Biological evaluation included determination of activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. Some of the novel compounds presented high activity in vitro against chloroquine-resistant strains, more potent than chloroquine and clotrimazole. Computational studies revealed that the activity is likely due to the ability of the compounds to assume a multisite iron coordinating geometry.
Gemma
Sandra
S
European Research Centre for Drug Discovery & Development, Università di Siena, via Aldo Moro, 53100 Siena, Italy.
Kukreja
Gagan
G
Campiani
Giuseppe
G
Butini
Stefania
S
Bernetti
Matteo
M
Joshi
Bhupendra P
BP
Savini
Luisa
L
Basilico
Nicoletta
N
Taramelli
Donatella
D
Yardley
Vanessa
V
Bertamino
Alessia
A
Novellino
Ettore
E
Persico
Marco
M
Catalanotti
Bruno
B
Fattorusso
Caterina
C
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002738:Chloroquine / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology; D019281:Dimerization; D015195:Drug Design; D004351:Drug Resistance; D007477:Ions; D008670:Metals / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000378:metabolism*
D000962:Antimalarials; D007477:Ions; D008670:Metals; D010879:Piperazines; D000077489:Piperazine; D002738:Chloroquine; D003022:Clotrimazole