Evaluation of Water‐Soluble Mannich Base Prodrugs of 2,3,4,5‐Tetrahydroazepino[4,3‐<i>b</i>]indol‐1(6<i>H</i>)‐one as Multitarget‐Directed Agents for Alzheimer's Disease
Rosa Purgatorio, Modesto de Candia, Marco Catto, Mariagrazia Rullo, Leonardo Pisani, Nunzio Denora, Antonio Carrieri, Alisa A. Nevskaya, Leonid G. Voskressensky, Cosimo Altomare
Abstract
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‐tetrahydroazepino[4,3‐ b ]indol‐1(6 H )‐one ( 1 ), a human butyrylcholinesterase inhibitor (hBChE, IC 50 13 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 (IC 50 =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 vivo Alzheimer's disease models.