Evaluation of Water-Soluble Mannich Base Prodrugs of 2,3,4,5-Tetrahydroazepino[4,3-b]indol-1(6H)-one as Multitarget-Directed Agents for Alzheimer's Disease

Different Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6-phenethyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1), a human butyrylcholinesterase inhibitor (hBChE, IC5013 nM) and protective agent in NMDA-induced neurotoxicity, in in vivo assays. The N-(4-methylpiperazin-1-yl)methyl derivative 2 c showed a 50-fold increase in solubility in pH 7.4-buffered solution, high stability in serum and (half-life >24 h) and rapid (<3 min) conversion to 1 at acidic pH. Although less active than 1, 2 c retained moderate hBChE inhibition (IC50=3.35 μM) and a significant protective effect against NMDA-induced neurotoxicity at 0.1 μM. Moreover, 2 c resulted a weaker serum albumin binder than 1, could pass the blood–brain barrier, and exerted negligible cytotoxicity on HepG2 cells. These findings suggest that 2 c could be a water-soluble prodrug candidate of 1 for oral administration or a slow-release injectable derivative in in vivoAlzheimer's disease models. © 2020 Wiley-VCH GmbH

Authors
Purgatorio R.1 , De Candia M. , Catto M.1 , Rullo M.1 , Pisani L.1 , Denora N.1 , Carrieri A.1 , Nevskaya A.A. 2 , Voskressensky L.G. 2 , Altomare C.D.1
Journal
Publisher
John Wiley and Sons Ltd
Number of issue
3
Language
English
Pages
589-598
Status
Published
Volume
16
Year
2021
Organizations
  • 1 Department of Pharmacy-Drug-Sciences, University of Bari Aldo Moro, Via E. Orabona 4, Bari, 70125, Italy
  • 2 Organic Chemistry Department, RUDN University, Miklukho-Maklai St. 6, Moscow, 117198, Russian Federation
Keywords
Alzheimer disease; azepinoindolone derivatives; butyrylcholinesterase inhibitor; Mannich bases; water-soluble prodrugs
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