Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further structure-activity relationships, in vivo studies, and preliminary toxicity profiling.
Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.
European Research Centre for Drug Discovery and Development (NatSynDrugs), Università di Siena , Via A. Moro, 53100 Siena, Italy.
Sandra
S
Gemma
Caterina
C
Camodeca
Salvatore
S
Sanna Coccone
Bhupendra P
BP
Joshi
Matteo
M
Bernetti
Vittoria
V
Moretti
Simone
S
Brogi
Maria Cruz
MC
Bonache de Marcos
Luisa
L
Savini
Donatella
D
Taramelli
Nicoletta
N
Basilico
Silvia
S
Parapini
Matthias
M
Rottmann
Reto
R
Brun
Stefania
S
Lamponi
Silvio
S
Caccia
Giovanna
G
Guiso
Robert L
RL
Summers
Rowena E
RE
Martin
Simona
S
Saponara
Beatrice
B
Gorelli
Ettore
E
Novellino
Giuseppe
G
Campiani
Stefania
S
Butini
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D002738:Chloroquine / Q000493:pharmacokinetics / Q000494:pharmacology; D003022:Clotrimazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D006207:Half-Life; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017725:Ventricular Pressure / Q000187:drug effects; D014982:Xenopus laevis
D000634:Aminoquinolines; D000962:Antimalarials; D006420:Hemeproteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D010879:Piperazines; D015800:Protozoan Proteins; C020753:hemozoin; D002738:Chloroquine; D003022:Clotrimazole; C001920:4-aminoquinoline