Secondary metabolites obtained from natural sources are medicinally relevant molecules. About one-third of all FDA-approved drugs are derived from or based on natural products, which suggests that molecular optimization is often required for translation from benchtop to clinical practice. Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease highly prevalent in Latin America. It has a significant impact on socioeconomic indicators and is not easily cured by the two currently available drugs, benznidazole and nifurtimox. Considering the importance of developing new bioactive molecules based on natural products, this article reviews 21 years of literature reports on the semisynthesis and total synthesis of new compounds targeting T. cruzi. From 1997 to 2018, sixty-six articles reporting five hundred and thirty-seven molecules active against different strains and life stages of the parasite were published. Quinones, alkaloids, terpenes, and lignans were the four largest classes of derivatives, the majority of which had IC₅₀ values low enough to indicate that natural product derivatives can be an important source of potential new drugs to treat Chagas disease. We highlight important molecules in each secondary metabolite class, discussing factors such as selectivity and the basis for their design. An assessment of drug-likeness parameters was performed, which might prove useful for selecting lead compounds for preclinical drug studies.

从天然来源获得的次生代谢产物是医学上相关的分子。在所有FDA批准的药物中，约有三分之一源自或基于天然产物，这表明从台式到临床实践的翻译通常需要分子优化。由克鲁斯锥虫引起的南美锥虫病是在拉丁美洲高度流行的一种被忽视的热带病。它对社会经济指标具有重大影响，并且不易被目前可用的两种药物苯并硝唑和硝呋替莫昔治愈。考虑到开发基于天然产物的新生物活性分子的重要性，本文回顾了21年有关针对克鲁氏梭菌的新化合物的半合成和全合成的文献报道。。从1997年到2018年，发表了66篇文章，报道了537种对不同菌株和生命阶段的寄生虫具有活性的分子。醌，生物碱，萜烯和木脂素是四大类衍生物，其中大多数的IC ₅₀值足够低，表明天然产物衍生物可能是治疗南美锥虫病的潜在新药的重要来源。我们重点介绍了每个次级代谢产物类别中的重要分子，并讨论了诸如选择性及其设计依据等因素。对药物相似性参数进行了评估，这可能对于选择临床前药物研究的先导化合物很有用。