Haematin-Quinoline interactions and structure-activity relationships in the antimalarial chloroquine and related compounds
Catherine H. Kaschula · Open University of Cape Town (University of Cape Town) · 2002
The nature of the ferriprotoporphyrin IX (Fe(III)PPIX) antimalarial drug target and its interactions with aminoquinolines was investigated spectrophotometrically.Fe(III)PPIX was found to be extensively dimerised in aqueous solution (log Ko = 7.2 ± 0.2) and is proposed to exist as a stacked, 1t-1t dimer and not a Il-oXO dimer as previously thought.Sensitivity of the spectrum charge transfer region of the visible spectrum to pH further conforms that the dimer is not a Il-oXO dimer.A series of 17 synthesised compounds and 7 commercially available quinolines were investigated for their ability to interact with Fe(III)PPIX, inhibit 13haematin formation and for anti plasmodial activity against the 010 chloroquine-sensitive strain of malaria parasite.2-And 4-aminoquinoline were found to be unique in their ability to form strong complexes with Fe{III)PPIX (log K = 4.23 ± 0.02 and 4.49 ± 0.01 respectively) whilst quinoline, 3-, 5-, 6-and 8-aminoquinoline fail to fonn any detectible complexes with Fe(III)PPIX.The association with Fe(III)PPIX was found to be a necessary, but not sufficient requirement for inhibition of J3-haematin fonnation.The presence of a chloro-group at the 7position on the quinoline ring was found to be a requirement for this inhibition.In tum, inhibition of J3-haematin fonnation was found to be a necessary but not sufficient requirement for antiplasmodial activity.A basic side-chain was found to be the additional component needed for this activity.In a further series of eleven N 2 -(7-X-4-quinolinyl)-N 1 ,N 1 -diethyl-1,2ethanediamines where X = NH2, OH, OCHs, H, CHs, F, I, 8r, CI, CFs and N02 that were / synthesised, it was found that the pKa of the quinoline ring nitrogen and the tertiary amino nitrogen are both lowered by electron withdrawing sustituents at the 7-posiiton.The quinoline nitrogen pKa ranges from 6.28 in the nitro derivative to 8.36 in the amino derivative, whilst the tertiary amino nitrogen has a pK a ranging between 7.65 in the trifluoromethyl derivative and 10.02 in the amino derivative.Calculation suggests that the resulting pH trapping of these compounds in the paraSite food vacuole ranges between about 9% of that observed in chloroquine for the nitro derivative and 97% in the amino derivative.It was found that the critical structural feature in chloroquine and related 4-aminoquinolines responsible for strong J3-haematin inhibition is the chloro-group at the 7-position on the 4-aminoquinoline ring.In the series. of eleven 7-substituted 4-aminoquinolines a direct correlation was observed between anti plasmodial activity which had been nonnalised for the extent of pH trapping and J3-haematin inhibitory activity (rZ = 0.83, p = 0.004).The J3-haematin inhibitory activity was found to correlate with the Fe(III)PPIX-quinoline association constant and the Hammett constant of the substituent at the 7-posiiton.The aSSOciation constant was found to correlate with the lipophilicity of the group at the 7 -position.