Vennerstrom J L, Ager A L, Dorn A, Andersen S L, Gerena L, Ridley R G, Milhous W K
College of Pharmacy, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, Nebraska 68198-6025, USA.
J Med Chem. 1998 Oct 22;41(22):4360-4. doi: 10.1021/jm9803828.
N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were significantly more potent against the chloroquine-resistant W2 clone compared to the chloroquine-sensitive D6 clone. For bisquinolines 1-11 there was no relationship between the length of the bisquinoline heteroalkane bridge and antimalarial activity and no correlation between in vitro and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquinolines with alkylamine bridges against P. berghei in vivo. Bisquinolines 1-10 were potent inhibitors of hematin polymerization with IC50 values falling in the narrow range of 5-20 microM, and there was a correlation between potency of inhibition of hematin polymerization and inhibition of parasite growth. Compared to alkane-bridged bisquinolines (Vennerstrom et al., 1992), none of these heteroalkane-bridged bisquinolines had sufficient antimalarial activity to warrant further investigation of the series.
合成了N,N-双(7-氯喹啉-4-基)杂烷二胺1-11，并对其进行体外抗恶性疟原虫及体内抗伯氏疟原虫的筛选。这些双喹啉对体外恶性疟原虫的IC50值为1至100 nM。11种双喹啉中有6种对氯喹耐药的W2克隆的活性明显高于氯喹敏感的D6克隆。对于双喹啉1-11，双喹啉杂烷桥的长度与抗疟活性之间没有关系，体外和体内抗疟活性之间也没有相关性。带有烷基醚和哌嗪桥的双喹啉在体内对伯氏疟原虫的效果明显优于带有烷基胺桥的双喹啉。双喹啉1-10是血红素聚合的有效抑制剂，IC50值在5-20 microM的窄范围内，并且血红素聚合抑制效力与寄生虫生长抑制之间存在相关性。与烷烃桥连双喹啉（Vennerstrom等人，1992年）相比，这些杂烷烃桥连双喹啉均没有足够的抗疟活性来保证对该系列进行进一步研究。
