Toward a novel metal-based chemotherapy against tropical diseases.: 7.: Synthesis and in vitro antimalarial activity of new gold-chloroquine complexes

A number of new Au(I) and Au(III) complexes of chloroquine (CQ) have been prepared, characterized, and evaluated in vitro against several strains of Plasmodium falciparum. [(CQ)Au(PPh3)] [NO3] (2) was synthesized by reaction of AuCl(PPh3) with AgNO3 followed by treatment with CQ. Similar reactions of AuCl(PR3) (R = Me, Et) with KPF6 and CQ yielded [(CQ)Au(PMe3)] [PF6] (3), and [(CQ)Au(PEt3)] [PF6] (4), respectively. KAuCl4 reacted with CQ to produce the Au(III) complex [(CQ)(2)Au(CI)(2)]Cl (5), which in turn formed [(CQ)Au(Cl)(SR)-(Et2O)]Cl (6) by reaction with 1-thio-beta-D-glucose-2,3,4,6-tetraacetate (SRH). The new compounds were characterized by a combination of elemental analysis, fast atom bombardment mass spectrometry (FAB-MS), and NMR spectroscopy. All the complexes display in vitro activity against CQ-sensitive and CQ-resistant strains of Plasmodium falciparum. The highest activity for this series was obtained for complex 4, which is 5 times more active than chloroquine diphosphate (CQDP) against the CQ-resistant strain FcB1. On preincubation of noninfected red blood cells with complexes 1, 5, and 6, protection against subsequent infection was observed in some cases. No clear structure- activity correlations could be established for this series of compounds.