Table_1_Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites.XLS

We have demonstrated previously that amino-artemisinins including artemiside and artemisone in which an amino group replaces the oxygen-bearing substituents attached to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether and artesunate, display potent activities in vitro against the asexual blood stages of Plasmodium falciparum (Pf). In particular, the compounds are active against late blood stage Pf gametocytes, and are strongly synergistic in combination with the redox active drug methylene blue. In order to fortify the eventual selection of optimum amino-artemisinins for development into new triple combination therapies also active against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins based on the easily accessible and inexpensive DHA-piperazine. The latter was converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the hitherto most active amino-artemisinins artemiside and artemisone against asexual and sexual blood stages of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins bearing aryl-urea and -amide groups are potently active against both asexual, and late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early results indicate these compounds tend not to display reduced susceptibility against parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside and artemisone will enable the development of new combination therapies that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking capabilities and may be effective against artemisinin resistant falciparum malaria.

本团队此前已证实：以氨基取代当前临床青蒿素类衍生物——双氢青蒿素（dihydroartemisinin, DHA）、蒿甲醚、青蒿琥酯——C-10位含氧取代基所得到的氨基青蒿素类（amino-artemisinins）化合物，包括青蒿素苷（artemiside）与青蒿素酮（artemisone），在体外对恶性疟原虫（Plasmodium falciparum, Pf）的无性血液阶段具有强效抗疟活性。尤为重要的是，此类化合物对血液晚期阶段的恶性疟原虫配子体具有活性，且与氧化还原活性药物亚甲蓝联用时可展现出显著的协同效应。为了最终筛选出最优的氨基青蒿素类化合物，用于开发同时对抗青蒿素耐药恶性疟原虫突变株的新型三联复方疗法，本团队以易得且廉价的DHA-哌嗪为母核，合成了一系列新型氨基青蒿素类衍生物，并将该母核转化为烷基、芳基磺酰胺类、脲类以及酰胺类衍生物。本研究将此类衍生物与对照药物DHA、迄今活性最强的氨基青蒿素类化合物青蒿素苷与青蒿素酮一同开展活性筛选，测试对象涵盖恶性疟原虫的无性与有性血液阶段，以及伯氏疟原虫（Plasmodium berghei, Pb）肝脏阶段的子孢子。多款携带芳基脲与酰胺基团的新型氨基青蒿素类化合物，对无性血液阶段与晚期血液阶段的疟原虫配子体均展现出强效活性，半数抑制浓度（half maximal inhibitory concentration, IC50）为0.4~1.0 nM。尽管此类衍生物的活性优于青蒿素苷（IC50=1.5 nM）与青蒿素酮（IC50=42.4 nM），但后两者对伯氏疟原虫肝脏阶段子孢子的活性更强，其中青蒿素酮的IC50为28 nM。此外，初步研究结果显示，此类化合物对携带青蒿素耐药恶性疟原虫标志性突变——Pf Kelch 13桨域（propeller domain）C580Y突变——的疟原虫，不易出现敏感性降低的情况。综上，包括青蒿素苷与青蒿素酮在内的氨基青蒿素类化合物的问世，将助力新型复方抗疟疗法的开发：此类疗法凭借氨基青蒿素组分本身的特性，即可具备天然的传播阻断能力，且可有效对抗青蒿素耐药性恶性疟。