Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine [compound 1], isochondodendrine [compound 2], and 2′-norcocsuline [compound 3]) isolated from the Triclisia subcordata Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semisynthetic analogues (compounds 4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant Plasmodium falciparum strain were determined using a SYBR green 1 fluorescence assay. The in vivo antimalarial activity of cycleanine is then investigated in suppressive, prophylactic, and curative murine malaria models after infection with a chloroquine-sensitive Plasmodium berghei strain. BBIQ alkaloids (compounds 1 to 5) exerted in vitro antiplasmodial activities with 50% inhibitory concentration (IC₅₀) at low micromolar concentrations and the two semisynthetic cycleanine analogues showed an improved potency and selectivity compared to those of cycleanine. At oral doses of 25 and 50 mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitemia and increased mean survival times significantly compared to those of the control groups. The metabolites and metabolic pathways of cycleanine were also studied using high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastric administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these in vitro and in vivo results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.

中文翻译：

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抗疟疾Cyclanine的体内功效和代谢以及半合成类似物的体外抗血浆活性提高

双苄基异喹啉（BBIQ）生物碱是一组具有多种生物活性的天然产物。在这项研究中，从Triclisia subcordata Oliv中分离出的三种BBIQ生物碱（环己胺[化合物1]，异佛手鱼藤碱[化合物2]和2'-降糖球碱[化合物3]）的体外抗血浆活性。在尼日利亚，将传统上用于治疗疟疾的药用植物与两种环己胺的半合成类似物（化合物4和5）进行了研究。使用SYBR green 1荧光测定法测定了对耐氯喹的恶性疟原虫菌株的抗增殖作用。在体内然后，在氯喹敏感的伯氏疟原虫感染后，在抑制性，预防性和治愈性鼠类疟疾模型中研究了Cyclanine的抗疟活性。BBIQ生物碱（化合物1至5）具有50％抑制浓度的体外抗血浆活性（IC ₅₀）在较低的微摩尔浓度下，与环己胺相比，两种半合成环烷类似物显示出更高的效价和选择性。与对照组相比，口服感染剂量为25和50 mg / kg体重的小鼠时，Cyclanine抑制了寄生虫血症的水平，并且平均存活时间显着增加。还使用高效液相色谱-电喷雾电离-串联质谱法研究了Cyclanine的代谢物和代谢途径。胃内注射Cyclanine后，在大鼠中检测到十二种新型代谢产物。已证明环己胺的代谢途径涉及羟基化，脱氢和脱甲基。总体而言，这些体外和体内 研究结果为进一步评估环丙氨酸及其类似物提供了依据。