| Abstract
| - Antiplasmodial activities versus the chloroquine sensitive D10 strain of Plasmodium falciparumof a series of N,N1-diethyl-N-(4-quinolinyl)-1,2-ethanediamines with 11 different substituentsat the 7-position on the quinoline ring have been investigated in vitro. Electron-withdrawinggroups at the 7-position have been shown to lower the pKa of both the quinoline ring nitrogenatom and the tertiary amino nitrogen in the alkyl side chain. The quinoline nitrogen pKa rangesfrom 6.28 in the nitro derivative to 8.36 in the amino derivative, while the tertiary aminonitrogen has a pKa ranging between 7.65 in the trifluoromethyl derivative and 10.02 in theamino derivative. Calculation suggests that the resulting pH trapping of these compounds inthe parasite food vacuole ranges between about 7% of that observed in chloroquine for theNO2 derivative and 97% in the amino derivative. A direct proportionality between antiplasmodial activity normalized for pH trapping and β-hematin inhibitory activity was observed.Activity could not be correlated with any other observed physical parameter. The β-hematininhibitory activity of these derivatives appears to correlate with both the hematin−quinolineassociation constant and the electron-withdrawing capacity of the group at the 7-position(Hammett constant). For the compounds under investigation, the hematin association constantis in turn influenced by the lipophilicity of the group at the 7-position.
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