Semisynthetic\nEcdysteroid Cinnamate Esters and <i>tert</i>-Butyl Oxime\nEther Derivatives with Trypanocidal Activity

The parasite <i>Trypanosoma cruzi</i> is the\ncausative\nagent of Chagas disease, a neglected tropical disease that affects\nthe lives of millions of indigenous people in Latin America. As medications\nto treat Chagas disease are limited to the application of benznidazole\nand nifurtimox, which are not ideal treatments for the chronic stage\nof the disease, the search for new antichagasic drug candidates is\nan important need. Ecdysone has previously been shown to interfere\nwith the life cycle of <i>T. cruzi</i>. Here, we report\nthe biological profiling and subsequent semisynthetic structure optimization\nof 47 ecdysteroids against <i>T. cruzi</i> with the aim\nof identifying selective trypanocidal ecdysteroids. Two moderately\ntrypanocidal pharmacophores were identified: ecdysteroids containing\na 6-<i>tert</i>-butyl oxime ether and a cinnamic ester moiety.\nThese functional groups were combined into the structures of four\nnew semisynthetic ecdysteroids (<b>44</b>–<b>47</b>), among which <b>44</b> exerted potent and selective trypanocidal\nactivity (IC<sub>50</sub> < 2 μM). Cellular infection assays\nshowed that ecdysteroid <b>44</b> potently and efficiently inhibited\namastigote replication as determined by trypomastigote release after\ncellular infection with an IC<sub>50</sub> of 2.7 ± 0.1 μM.\nThe compound was similarly potent to benznidazole (IC<sub>50</sub> = 3.8 ± 0.7 μM) and more than 5-fold more cytotoxic toward <i>T. cruzi</i> over RAW264.7 host macrophages. Overall, the ecdysteroid\ncinnamate ester <b>44</b> is a novel trypanocidal lead structure\nthat needs to be further characterized in follow-up studies.