Herein we report in vitro metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer’s disease therapy.

中文翻译：

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靶向神经退行性疾病的多功能单胺氧化酶抑制剂的体外和计算机模拟ADME-Tox分析及安全性意义

在此我们进行体外报道人肝微粒体（HLM）的代谢稳定性，与细胞色素P450同工酶（CYP3A4，CYP2D6和CYP2C9）的相互作用以及我们最新的多靶标定向配体PF9601N和ASS234对HEK-293，HepG2，Huh7和WTIIB细胞系的细胞毒性分析，并且乐于助人。根据这些结果，我们得出结论：（1）与非常不稳定的ASS234相比，PF9601N和contilisant在HLM分析中代谢稳定。（2）在所有测试浓度下，PF9601N降低CYP3A4活性；在最高浓度下，仅通过ASS234和有益剂降低CYP3A4活性；CYP2D6活性在1,10和25μM时被ASS234降低，在10和25μM时被PF9601N降低，而在相同的浓度下，康托利特​​增加了它的活性; CYP2C9被这三种化合物抑制。（3）相容剂在最宽的浓度范围内均不影响细胞活力：HEK-293细胞上最高10μM，Huh7细胞上最高30μM，HepG2细胞上最高50μM，HepG2细胞上最高30或100μM WTIIB细胞。基于这些结果，我们选择了一种可作为代谢稳定且无毒的先导化合物，用于阿尔茨海默氏病治疗的进一步研究。