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

Aiming at addressing the poor aqueous solubility in in vivo assays of the recently disclosed 6-phenethyl-2,3,4,5- tetrahydroazepino[4,3-b]indol-1(6H)-one (1), human butyrylcholinesterase inhibitor (hBChE, IC5013 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 M) and a significant protective effect against NMDA-induced neurotoxicity at 0.1 M. 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 1 for oral administration or a slow-release injectable derivative in in vivo AD models.