Kelly Jane Xu, Winter Rolf, Peyton David H, Hinrichs David J, Riscoe Michael
Department of Chemistry, Portland State University, Portland, Oregon 97207-0751, USA.
Antimicrob Agents Chemother. 2002 Jan;46(1):144-50. doi: 10.1128/AAC.46.1.144-150.2002.
Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-omega-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R(2) = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC(50)) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 x 10(5) and 9.02 x 10(5) M(-1), respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.
羟基氧杂蒽酮已被确认为新型抗疟药物。据信这些化合物通过与血红素络合并抑制疟原虫色素形成来发挥其活性。人们对氧杂蒽酮结构进行修饰以提高其抗疟活性。通过连接带有可质子化氮原子的R基团，以通过与金属卟啉的丙酸侧链的离子相互作用增强血红素亲和力，并促进药物在寄生虫食物泡中的积累。制备并评估了一系列侧链碳原子数从2到8的3,6-双-ω-二乙氨基烷氧基氧杂蒽酮。对每种衍生物的血红素亲和力的测量显示亲和力与抗疟效力之间存在强相关性（R(2) = 0.97）。该系列中活性最高的两种化合物含有5个和6个碳原子的侧链，在体外对氯喹敏感和多药耐药的恶性疟原虫菌株表现出低纳摩尔的50%抑制浓度（IC(50)）值。在类似条件下，这两种氧杂蒽酮均比氯喹或奎宁表现出更强的血红素亲和力（分别为8.26 x 10(5)和9.02 x 10(5) M(-1)），并且似乎以独特的方式与血红素络合。
