Purgatorio_2021_ChemMedChem_16_589

Aiming at addressing the poor aqueous solubility in in vivo assays of the recently disclosed 6-phenetyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1), human butyrylcholinesterase inhibitor (hBChE, IC50 13 nM) and protective agent in NMDA-induced neurotoxicity, different Mannich base derivatives were studied. The N-(4-methylpiperazin-1-yl)methyl derivative 2c showed a 50-fold increase of solubility in pH 7.4 buffered solution, high stability in serum and pH 7.4 (half-life> 24 h) and rapid (< 3 min) conversion to 1 at acidic pH. Albeit less active than 1, 2c retained moderate hBChE inhibition (IC50 3.35 mM) and a significant protective effect against NMDA-induced neurotoxicity at 0.1 mM. Moreover, 2c resulted a weaker serum albumin binder than 1, a blood-brain barrier permeant, and exerted negligible cytotoxicity on HepG2 cells.These findings suggest that 2c could be a water-soluble prodrug candidate of 1for oral administration or a slow-release injectable derivativein in vivoAD models.