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 |
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Authors: | Dr Rosa Purgatorio Dr Modesto de Candia Dr Marco Catto Dr Mariagrazia Rullo Dr Leonardo Pisani Prof Nunzio Denora Prof Antonio Carrieri Alisa A Nevskaya Prof Leonid G Voskressensky Prof Cosimo D Altomare |
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Affiliation: | 1. Department of Pharmacy-Drug-Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy;2. Organic Chemistry Department, RUDN University, Miklukho-Maklai St. 6, Moscow, 117198 Russia |
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Abstract: | 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-tetrahydroazepino4,3-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. |
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Keywords: | Alzheimer disease azepinoindolone derivatives butyrylcholinesterase inhibitor Mannich bases water-soluble prodrugs |
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