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Design, Synthesis and Biological Activity of C3 Hemisynthetic Triterpenic Esters as Novel Antitrypanosomal Hits
ChemistryOpen ( IF 2.5 ) Pub Date : 2021-09-09 , DOI: 10.1002/open.202100159 Laura Schioppa 1 , Claire Beaufay 1 , Natacha Bonneau 1 , Marianela Sanchez 2 , Cynthia Girardi 1 , Aurélie Leverrier 2 , Sergio Ortiz 1 , Jorge Palermo 2 , Jacques H Poupaert 3 , Joëlle Quetin-Leclercq 1
ChemistryOpen ( IF 2.5 ) Pub Date : 2021-09-09 , DOI: 10.1002/open.202100159 Laura Schioppa 1 , Claire Beaufay 1 , Natacha Bonneau 1 , Marianela Sanchez 2 , Cynthia Girardi 1 , Aurélie Leverrier 2 , Sergio Ortiz 1 , Jorge Palermo 2 , Jacques H Poupaert 3 , Joëlle Quetin-Leclercq 1
Affiliation
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Research for innovative drugs is crucial to contribute to parasitic infections control and eradication. Inspired by natural antiprotozoal triterpenes, a library of 12 hemisynthetic 3-O-arylalkyl esters was derived from ursolic and oleanolic acids through one-step synthesis. Compounds were tested on Trypanosoma, Leishmania and the WI38 cell line alongside with a set of triterpenic acids. Results showed that the triterpenic C3 esterification keeps the antitrypanosomal activity (IC50≈1.6–5.5 μm) while reducing the cytotoxicity compared to parent acids. Unsaturation of the ester alkyl chain leads to an activity loss interestingly kept when a sterically hindered group replaces the double bond or shields the ester group. An ursane/oleanane C3 hydroxylation was the only important feature for antileishmanial activity. Two candidates, dihydrocinnamoyl and 2-fluorophenylpropionyl ursolic acids, were tested on an acute mouse model of African trypanosomiasis with significant parasitemia reduction at day 5 post-infection for the dihydrocinnamoyl derivative. Further evaluation on other alkyl/protective groups should be investigated both in vitro and in vivo.
中文翻译：
作为抗锥虫新药的 C3 半合成三萜酯的设计、合成和生物活性
创新药物的研究对于控制和根除寄生虫感染至关重要。受天然抗原虫三萜的启发，通过一步合成从熊果酸和齐墩果酸中衍生出12 种半合成 3- O-芳基烷基酯库。这些化合物与一组三萜酸一起在锥虫、利什曼原虫和 WI38 细胞系上进行了测试。结果表明，与母体酸相比，三萜C3酯化保留了抗锥虫活性（IC 50 ≈1.6–5.5 μm ） ，同时降低了细胞毒性。当空间位阻基团取代双键或屏蔽酯基团时，酯烷基链的不饱和度会导致有趣的活性损失。乌苏烷/齐墩果烷 C3 羟基化是抗莱什曼尼活性的唯一重要特征。在非洲锥虫病急性小鼠模型上测试了两种候选物：二氢肉桂酰熊果酸和 2-氟苯基丙酰熊果酸，二氢肉桂酰衍生物感染后第 5 天寄生虫血症显着减少。应在体外和体内研究对其他烷基/保护基团的进一步评估。
更新日期：2021-09-09
中文翻译：
作为抗锥虫新药的 C3 半合成三萜酯的设计、合成和生物活性
创新药物的研究对于控制和根除寄生虫感染至关重要。受天然抗原虫三萜的启发，通过一步合成从熊果酸和齐墩果酸中衍生出12 种半合成 3- O-芳基烷基酯库。这些化合物与一组三萜酸一起在锥虫、利什曼原虫和 WI38 细胞系上进行了测试。结果表明，与母体酸相比，三萜C3酯化保留了抗锥虫活性（IC 50 ≈1.6–5.5 μm ） ，同时降低了细胞毒性。当空间位阻基团取代双键或屏蔽酯基团时，酯烷基链的不饱和度会导致有趣的活性损失。乌苏烷/齐墩果烷 C3 羟基化是抗莱什曼尼活性的唯一重要特征。在非洲锥虫病急性小鼠模型上测试了两种候选物：二氢肉桂酰熊果酸和 2-氟苯基丙酰熊果酸，二氢肉桂酰衍生物感染后第 5 天寄生虫血症显着减少。应在体外和体内研究对其他烷基/保护基团的进一步评估。
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