Abstract

Nonsteroidal aromatase inhibitors (NSAIs) are well-established drugs for the therapy of breast cancer. However, they display some serious side effects, and their efficacy can be compromised by the development of chemoresistance. Previously, we have reported different indazole-based carbamates and piperidine-sulphonamides as potent aromatase inhibitors. Starting from the most promising compounds, here we have synthesised new indazole and triazole derivatives and evaluated their biological activity as potential dual agents, targeting both the aromatase and the inducible nitric oxide synthase, being this last dysregulated in breast cancer. Furthermore, selected compounds were evaluated as antiproliferative and cytotoxic agents in the MCF-7 cell line. Moreover, considering the therapeutic diversity of azole-based compounds, all the synthesized compounds were also evaluated as antifungals on different Candida strains. A docking study, as well as molecular dynamics simulation, were carried out to shed light on the binding mode of the most interesting compound into the different target enzymes catalytic sites.

摘要

非甾体芳香酶抑制剂 (NSAI) 是用于治疗乳腺癌的成熟药物。然而，它们显示出一些严重的副作用，并且它们的功效会因化学抗性的发展而受到损害。以前，我们已经报道了不同的​​基于吲唑的氨基甲酸酯和哌啶-磺酰胺作为有效的芳香酶抑制剂。从最有希望的化合物开始，我们在这里合成了新的吲唑和三唑衍生物，并评估了它们作为潜在双重药物的生物活性，靶向芳香酶和诱导型一氧化氮合酶，这是乳腺癌中最后一个失调的化合物。此外，选定的化合物被评估为 MCF-7 细胞系中的抗增殖剂和细胞毒剂。此外，考虑到唑类化合物的治疗多样性，念珠菌菌株。进行了对接研究以及分子动力学模拟，以阐明最有趣的化合物与不同目标酶催化位点的结合模式。