Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
Antimicrob Agents Chemother. 2019 Mar 27;63(4). doi: 10.1128/AAC.02156-18. Print 2019 Apr.
More than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the protozoan parasite , is no longer just a problem for the American continents but has become a global health threat. Current therapies, i.e., nifurtimox and benznidazole (Bz), are far from being adequate, due to their undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypic evaluation in of a new class of imidazole compounds, which were discovered in a previous phenotypic screen against different trypanosomatids and were designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to that of Bz prompted a synthesis program of hit optimization and extended structure-activity relationship aimed at improving drug-like properties such as aqueous solubility, which resulted in additional hits with 50% inhibitory concentration (IC) values similar to that of Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC concentration, that were consistent with induced autophagy and osmotic stress, mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP levels, confirming that inhibition of PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against constitutes a successful repurposing of research into inhibitors of mammalian PDEs.
在首次被描述 100 多年后，恰加斯病仍然在 21 个拉丁美洲国家流行，并已传播到其他大洲。事实上，这种由原生动物寄生虫引起的疾病不再仅仅是美洲大陆的问题，已成为全球健康威胁。目前的治疗方法，即硝呋替莫和苯并咪唑（Bz），由于其不良反应和在疾病慢性阶段缺乏疗效，远非理想。在这项工作中，我们对一类新的咪唑化合物进行了深入的表型评估，这些化合物是在之前针对不同的利什曼原虫的表型筛选中发现的，被设计为环磷酸腺苷磷酸二酯酶（PDEs）的潜在抑制剂。几种与 Bz 相似或优于 Bz 的活性得到证实，促使我们进行了针对优化和扩展结构-活性关系的合成计划，旨在提高药物样特性，如水溶性，这导致了具有与 Bz 相似的 50%抑制浓度（IC）值的其他命中化合物。我们进一步研究了代表性命中化合物 9 对血流中的锥虫的细胞作用。透射电子显微镜显示，在与 IC 浓度孵育仅 2 小时后，细胞发生了变化，这些变化与诱导的自噬和渗透应激一致，这些机制以前与 cAMP 信号有关。化合物 9 诱导细胞内和培养基中 cAMP 水平显著升高，证实抑制 PDE(s) 是其作用机制的一部分。该咪唑类 PDE 抑制剂对 具有强大而选择性的活性，成功地重新利用了对哺乳动物 PDE 抑制剂的研究。
