Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use—artemether and artesunate—induces quiescence in ring‐stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11‐azaartemisinin 5 and selected N‐sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug‐sensitive Pf NF54 and drug‐resistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC₅₀ values <10.5 nm. The p‐trifluoromethylbenzenesulfonyl‐11‐azaartemisinin derivative 11 [(4′‐trifluoromethyl)benzenesulfonylazaartemisinin] was the most active, with IC₅₀ values between 2 and 3 nm. The compounds were screened against Pf NF54 early and transmissible late intraerythrocytic‐stage gametocytes using luciferase and parasite lactate dehydrogenase (pLDH) assays. The 2′‐thienylsulfonyl derivative 16 (2′‐thiophenesulfonylazaartemisinin) was notably active against late‐stage (IV–V) gametocytes with an IC₅₀ value of 8.7 nm. All compounds were relatively nontoxic to human fetal lung WI‐38 fibroblasts, showing selectivity indices of >2000 toward asexual parasites. Overall, the readily accessible 11‐azaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisinin‐resistant parasites.

中文翻译：

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11-氮杂青蒿素和N-磺酰基衍生物对无性和可传播疟疾寄生虫的活性

双氢青蒿素（DHA）本身使用，或作为当前临床使用的其他青蒿素（蒿甲醚和青蒿琥酯）在体内产生的活性药物，会导致恶性疟原虫（Pf）的环期寄生虫静止。静止的诱导与青蒿素抗性有关。因此，我们转向了结构上完全不同的青蒿素，这些青蒿素不能在代谢中提供DHA。因此，针对药物敏感性Pf NF54和耐药性K1和W2寄生虫的红细胞内无性期筛选了11-氮杂青蒿素5和选定的N-磺酰基衍生物。表现出的针对所有三种菌株的最明显的活动，使用IC ₅₀值<10.5 n m。所述p -trifluoromethylbenzenesulfonyl -11- azaartemisinin衍生物11 [（4'-三氟甲基）benzenesulfonylazaartemisinin]是最活跃的，具有IC ₅₀ 2和3 N之间的值米。使用萤光素酶和寄生虫乳酸脱氢酶（pLDH）分析筛选了针对Pf NF54早期和可传播晚期红细胞内阶段配子细胞的化合物。2'-噻吩磺酰基衍生物16（2'-噻吩磺酰氮杂青蒿素）对晚期（IV-V）配子细胞具有显着活性，IC ₅₀值为8.7 n m。所有化合物对人胎肺WI-38成纤维细胞均无毒，对无性寄生虫的选择性指数> 2000。总体而言，易于获得的11-氮杂青蒿素5和磺酰基衍生物11和16代表了进一步发展的潜在候选物，特别是对青蒿素耐药性寄生虫的传播阻断。