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United States Department of Agriculture

Agricultural Research Service

Title: Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

item Khan, M.o. Faruk
item Levi, Mark
item Tekwani, Babu
item Khan, Shabana
item Kimura, Eiichi
item Borne, Ronald

Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/18/2009
Publication Date: 1/26/2009
Citation: Khan, M., Levi, M.S., Tekwani, B.L., Khan, S.I., Kimura, E., Borne, R.F. 2009. Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs. Antimicrobial Agents and Chemotherapy. 53(4):1320-1324.

Interpretive Summary: A cyclone 4-aminoquinoline, which acts through inhibition of b-hematin formation, showed activity against chloroquine resistant and susceptible strains of Plasmodium falciparum.

Technical Abstract: In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to anti-malarial agents we synthesized three cyclen analogs of chloroquine (4,6,7). Compound 4 displays the most potent in vitro and in vivo antimalarial activities. It displays an IC50 of 7.5 nM against D6 (chloroquine sensitive) clone and 19.2 nM against W2 (chloroquine resistant) clone of Plasmodium falciparum, which are comparable to that of artemisinin (IC50 10.6 nM and 5.0 nM, respectively) and higher than chloroquine (IC50 10.7 nM and 87.2 nM, respectively) without any evidence of cytotoxicity to mammalian cells indicating a high selectivity index (SI >1333 against D6 and >521 against W2 clone). Potent antimalarial activities of compound 4 against chloroquine and mefloquine resistant strains of P. falciparum have also been confirmed by in vitro 3H-hypoxanthine incorporation assay. In vivo antimalarial activity of compound 4, as determined in P. berghei infected mice, is comparable to that of chloroquine (ED50 less than or equal to 1.1 mg/kg p.o.); no apparent toxicity has been observed up to the highest dose (3x30 mg/kg) tested. Compound 4 inhibits in vitro hemozoin (ß-hematin) formation with an IC50 of 1.1 µM, which is about 10-fold more potent than that of chloroquine (IC50 9.5 µM). Compound 4 also shows potent in vitro inhibitory activity against the Leishmania donovani promastigotes (IC50 7.1 µM) which is comparable to that of pentamidine (IC50 3.5 µM). Overall, this article describes the discovery of a new class of cyclen 4-aminochloroquinolin analogs as potent antimalarial and antileishmanial drugs.

Last Modified: 10/16/2017
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