School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece.
Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
Curr Pharm Des. 2020;26(8):838-866. doi: 10.2174/1381612826666200210150127.
In this report, we extend the SAR analysis of a number of lipophilic guanylhydrazone analogues with respect to in vitro growth inhibition of Trypanosoma brucei and Trypanosoma cruzi. Sleeping sickness and Chagas disease, caused by the tropical parasites T. brucei and T. cruzi, constitute a significant socioeconomic burden in low-income countries of sub-Saharan Africa and Latin America, respectively. Drug development is underfunded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern. The synthesis of adamantane-based compounds that have potential as antitrypanosomal agents is extensively reviewed. The critical role of the adamantane ring was further investigated by synthesizing and testing a number of novel lipophilic guanylhydrazones. The introduction of hydrophobic bulky substituents onto the adamantane ring generated the most active analogues, illustrating the synergistic effect of the lipophilic character of the C1 side chain and guanylhydrazone moiety on trypanocidal activity. The n-decyl C1-substituted compound G8 proved to be the most potent adamantane derivative against T. brucei with activity in the nanomolar range (EC50=90 nM). Molecular simulations were also performed to better understand the structure-activity relationships between the studied guanylhydrazone analogues and their potential enzyme target.
在本报告中，我们扩展了一系列脂溶性鸟苷腙类似物的 SAR 分析，以研究其对非洲撒哈拉以南低收入国家的热带寄生虫引起的昏睡病和恰加斯病（由寄生虫 T. brucei 和 T. cruzi 引起）的体外生长抑制作用。拉丁美洲）和拉丁美洲。药物开发资金不足。此外，目前的治疗方法已经过时且难以管理，而耐药性是一个新出现的问题。广泛综述了具有抗锥虫作用的金刚烷类化合物的合成。通过合成和测试一系列新型脂溶性鸟苷腙进一步研究了金刚烷环的关键作用。在金刚烷环上引入疏水性大体积取代基生成了最活跃的类似物，这说明了 C1 侧链和鸟苷腙部分的亲脂性对杀锥虫活性的协同作用。具有纳摩尔级（EC50=90 nM）活性的最有效金刚烷衍生物是 C1 取代的 n-癸基化合物 G8。还进行了分子模拟，以更好地理解所研究的鸟苷腙类似物与其潜在酶靶之间的结构-活性关系。
