Naphthylisoquinoline alkaloids, validated as hit multistage antiplasmodial natural products.
Naphthylisoquinoline alkaloids, validated as hit multistage antiplasmodial natural products.
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萘基异喹啉生物碱，被验证为热门的多级抗疟原虫天然产物。
DOI：
10.1016/j.ijpddr.2020.05.003
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Birkholtz,Lyn-Marie
中科院分区：
文献类型：
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作者：
Moyo,Phanankosi;Shamburger,William;vanderWatt,MariëtteE;Reader,Janette;deSousa,AnaCarolinaC;Egan,TimothyJ;Maharaj,VineshJ;Bringmann,Gerhard;Birkholtz,Lyn-Marie
针对红细胞内无性和有性恶性疟原虫寄生虫的多阶段抗疟药物的发现和开发对于实现消灭疟疾的宏伟目标至关重要。在这里，我们报告的验证萘异喹啉（NIQ）生物碱及其合成类似物作为多阶段活性抗疟药物候选人。共检测了30种化合物，其中17种化合物对药物敏感的P.恶性疟原虫（NF 54株）;其中15个保留了对一组耐药菌株的活性。这些化合物对HepG 2细胞显示出低的体外细胞毒性，选择性指数>10。所测试的化合物在体外对早期和晚期的P都表现出活性。在2 μM浓度下，对雄配子形成的抑制率>70%。此外，发现5种选定的化合物具有良好的溶解度（在pH 6.5的PBS中≥170 μM），而30 min后对人、小鼠和大鼠微粒体的代谢稳定性范围为>90%至>7%。Dioncophylline C（2a）是研究中的领跑者，显示出对无性寄生虫和配子体的活性，对氯喹缺乏交叉耐药性，溶解性良好，微粒体稳定性好。总体而言，这是第一份关于NIQs及其合成类似物的多阶段活性的报告，包括这类化合物诱导的杀配子和杀配子作用。
The discovery and development of multistage antimalarial drugs targeting intra-erythrocytic asexual and sexualPlasmodium falciparumparasites is of utmost importance to achieve the ambitious goal of malaria elimination. Here, we report the validation of naphthylisoquinoline (NIQ) alkaloids and their synthetic analogues as multistage active antimalarial drug candidates. A total of 30 compounds were tested, of which 17 exhibited IC50values <1 μM against drug-sensitiveP. falciparumparasites (NF54 strain); 15 of these retained activity against a panel of drug-resistant strains. These compounds showed lowin vitrocytotoxicity against HepG2 cells, with selectivity indices of >10. The tested compounds showed activityin vitroagainst both early- and late-stageP. falciparumgametocytes while blocking male gamete formation (>70% inhibition of exflagellation at 2 μM). Additionally, five selected compounds were found to have good solubility (≥170 μM in PBS at pH 6.5), while metabolic stability towards human, mouse, and rat microsomes ranged from >90% to >7% after 30 min. Dioncophylline C (2a) emerged as a front runner from the study, displaying activity against both asexual parasites and gametocytes, a lack of cross-resistance to chloroquine, good solubility, and microsomal stability. Overall, this is the first report on the multistage activity of NIQs and their synthetic analogues including gametocytocidal and gametocidal effects induced by this class of compounds.