De D, Bhaduri A P, Milhous W K
Department of Parasitology, Walter Reed Army Institute of Research, Washington, District of Columbia.
Am J Trop Med Hyg. 1993 Jul;49(1):113-20. doi: 10.4269/ajtmh.1993.49.113.
With the recent observations of efflux of chloroquine from Plasmodium falciparum and modulation of chloroquine resistance by calcium channel blockers, such as verapamil, a great deal of attention has been focused on the development of new modulators that can potentiate the efficacy of chloroquine. We report a new compound, WR268954, that has weak intrinsic antimalarial activity compared to chloroquine. In vitro, it increased the susceptibilities of chloroquine-resistant P. falciparum strains to chloroquine and quinine, but did not affect the chloroquine-susceptible strains. In the presence of 2,000 nM of WR268954, the 50% inhibitory concentration of chloroquine for drug-resistant P. falciparum decreased 90-fold in comparison with the control (chloroquine only). The same concentration of WR268954 increased the potentiation of chloroquine in resistant strains to a level approximately equivalent to that observed for the sensitive strain. This compound also potentiates the efficacy of quinine in drug-resistant parasites. However, WR268954 did not enhance the efficacy of mefloquine in the mefloquine-resistant parasites. In this report, the data show the synergistic effect of WR268954 on the antimalarial activity of chloroquine in drug-resistant strains of P. falciparum, but only an additive effect on drug-sensitive strains of parasites. Compound WR268954 belongs to a pyrrolidino alkane amine class whose in vitro chloroquine resistance modulator activity supports the basis for the synthesis of this class of compounds.
随着近期对恶性疟原虫氯喹外排以及钙通道阻滞剂（如维拉帕米）对氯喹耐药性调节的观察，大量关注集中于能增强氯喹疗效的新型调节剂的研发。我们报道了一种新化合物WR268954，与氯喹相比，其本身的抗疟活性较弱。在体外，它增加了氯喹耐药的恶性疟原虫菌株对氯喹和奎宁的敏感性，但对氯喹敏感菌株没有影响。在存在2000 nM的WR268954时，氯喹对耐药恶性疟原虫的50%抑制浓度与对照组（仅氯喹）相比降低了90倍。相同浓度的WR268954将耐药菌株中氯喹的增效作用提高到了与敏感菌株大致相当的水平。该化合物还增强了奎宁对耐药寄生虫的疗效。然而，WR268954并未增强甲氟喹对甲氟喹耐药寄生虫的疗效。在本报告中，数据显示WR268954对恶性疟原虫耐药菌株中氯喹抗疟活性具有协同作用，但对寄生虫敏感菌株仅具有相加作用。化合物WR268954属于吡咯烷基亚烷胺类，其体外氯喹耐药调节剂活性为这类化合物的合成提供了依据。
