An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection.
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection.
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DOI：
10.1371/journal.pntd.0009994
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发表时间：
2021-11
影响因子：
3.8
通讯作者：
Silber AM
中科院分区：
文献类型：
--
作者：
Cuevas-Hernández RI;Girard RMBM;Krstulović L;Bajić M;Silber AM
克氏锥虫是一种引起恰加斯病的血鞭毛寄生虫，在美洲影响着600-800万人。在这种疾病被描述一百多年后，现有的治疗克鲁兹旋毛虫感染的药物仍然很不令人满意。氯喹啉和芳胺基团分别存在于各种已报道的抗锥虫活性的化合物中。在这项工作中，我们评估了抗T。26个“嵌合”分子的CRUZI活性，这些分子结合了氯喹啉和嘧啶结构。在第一次筛选中，使用寄生虫的上鞭毛体形式作为临床相关阶段的代理，我们选择了表现更好的化合物7-chloro-4-[4-(4，5-dihydro-1H-imidazol-2-yl)phenoxy]quinoline(此处命名为A6)作为抗T。对哺乳动物细胞CHO-K1的IC50为137.9±17.3μM，对CHO-K1细胞的IC50为137.9±17.3μM。我们最初调查了与所选化合物相关的死亡机制。A6不触发磷脂酰丝氨酸暴露或质膜通透性。进一步的研究使我们观察到，在短期孵育(直到6小时)下，没有观察到线粒体功能的变化。但在较长的孵育时间(4d)下，A6可降低细胞内钙离子浓度，降低细胞内ATP水平，并使线粒体内膜电位崩溃。在对细胞周期进行分析后，我们还发现A6使寄生虫生长受阻于S期，从而影响寄生虫的增殖。最后，A6在纳摩尔浓度(IC50(Tryps)=26.7±3.7 nM)对哺乳动物宿主细胞感染过程中的感染形式有有效的抑制作用，其选择性指数(SI)为5,170。我们的数据表明，A6是对抗克氏锥虫的有希望的热门药物。查格斯病是由克氏锥虫引起的，属于动质体群的同鞭毛类寄生虫。这种疾病是美洲的地方病，然而，迁徙已经将CD传播到了其他大陆。据估计，每年有10,000多人死于感染克鲁兹旋毛虫，有800万人受到感染，因此有2500多万人面临感染这种疾病的风险。对镉的治疗不是很有效，主要是在疾病的慢性期，并由于目前使用的药物的毒性而造成不良反应。因此，迫切需要新的抗T。可恶的毒品。在这项工作中，我们评估了抗T。7-氯喹啉衍生的一系列化合物的克氏容量。我们更详细地研究了A6的作用方式，A6是一种芳香咪唑啉衍生物，对寄生虫的胞内形态(IC50(Try Ps)=26.7±3.7 nM)和高选择性指数(SI=5,170)显示出有效的影响。A6可能是一种很有前途的替代方案，用于开发一种新的有效治疗克鲁兹毛滴虫的方法。
Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6–8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T. cruzi infection remain largely unsatisfactory. Chloroquinoline and arylamidine moieties are separately found in various compounds reported for their anti-trypanosoma activities. In this work we evaluate the anti-T. cruzi activity of a collection of 26 “chimeric” molecules combining choroquinoline and amidine structures. In a first screening using epimastigote forms of the parasite as a proxy for the clinically relevant stages, we selected the compound 7-chloro-4-[4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy]quinoline (named here as A6) that performed better as an anti-T. cruzi compound (IC50 of 2.2 ± 0.3 μM) and showed a low toxicity for the mammalian cell CHO-K1 (CC50 of 137.9 ± 17.3 μM). We initially investigated the mechanism of death associated to the selected compound. The A6 did not trigger phosphatidylserine exposure or plasma membrane permeabilization. Further investigation led us to observe that under short-term incubations (until 6 hours), no alterations of mitochondrial function were observed. However, at longer incubation times (4 days), A6 was able to decrease the intracellular Ca2+, to diminish the intracellular ATP levels, and to collapse mitochondrial inner membrane potential. After analysing the cell cycle, we found as well that A6 produced an arrest in the S phase that impairs the parasite proliferation. Finally, A6 was effective against the infective forms of the parasite during the infection of the mammalian host cells at a nanomolar concentration (IC50(tryps) = 26.7 ± 3.7 nM), exhibiting a selectivity index (SI) of 5,170. Our data suggest that A6 is a promising hit against T. cruzi. Chagas disease (CD) is caused by Trypanosoma cruzi, a homoflagellate parasite that belongs to the group of kinetoplastids. This disease is endemic to the Americas, however, the migrations have spread CD to other continents. An estimated that more than 10,000 die each year due to infection by T. cruzi, 8 million people are infected and therefore more than 25 million people are at risk of acquiring the disease. Treatments to CD are not very efficient, mainly in the chronic phase of the disease and cause adverse effects due to the toxicity of drugs currently in use. Therefore, there is an urgent need for new anti-T. cruzi drugs. In this work we evaluate the anti-T. cruzi capacity of a series of compounds derived from 7-chloroquinolines. We study in more detail the mode of action of A6, an aromatic imizoline derivative that showed a potent effect on the intracellular forms of the parasite (IC50(tryps) = 26.7 ± 3.7 nM) and a high selectivity index (SI = 5,170). A6 could be a promising alternative for the development of a new efficient treatment against T. cruzi.
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影响因子：
3.7
作者：
Magdaleno A;Ahn IY;Paes LS;Silber AM
通讯作者：
Silber AM
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6.7
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影响因子：
1.3
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通讯作者：
CHIARI, E
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通讯作者：
Adak, Subrata
影响因子：
6.7
作者：
Muscia, Gisela C.;Cazorla, Silvia I.;Malchiodi, Emilio L.
通讯作者：
Malchiodi, Emilio L.