Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.

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Kelly JX, Smilkstein MJ, Cooper RA, Lane KD, Johnson RA, Janowsky A, Dodean RA, Hinrichs DJ, Winter R, Riscoe M

Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.

Antimicrob Agents Chemother. 2007 Nov;51(11):4133-40. Epub 2007 Sep 10.

PubMed ID
17846138 [ View in PubMed
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Abstract

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ChlorpheniramineHistamine H1 receptorIC 50 (nM)66N/AN/ADetails
DesipramineSodium-dependent noradrenaline transporterIC 50 (nM)4.2N/AN/ADetails
DesipramineSodium-dependent serotonin transporterIC 50 (nM)64N/AN/ADetails
ImipramineSodium-dependent dopamine transporterIC 50 (nM)25600N/AN/ADetails
ImipramineSodium-dependent noradrenaline transporterIC 50 (nM)74N/AN/ADetails
ImipramineSodium-dependent serotonin transporterIC 50 (nM)8N/AN/ADetails