Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer's disease.

Bioorganic & Medicinal Chemistry
Xin LuHao-Peng Sun

Abstract

In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.

Citations

Nov 24, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·You ZhouQingyou Xia
Sep 21, 2020·Journal of Cancer Research and Clinical Oncology·Takeshi IwasakiYoshinao Oda
Jul 28, 2020·BioMed Research International·Samuele MaramaiSamir Yahiaoui
Oct 30, 2019·Mini Reviews in Medicinal Chemistry·İrem BozbeyMehtap Uysal

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