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

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(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.

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

“…To corroborate this finding, the E / Z mixture of compound 1c was resolved by RP-HPLC separation. 51 The isolated Z - 1c was then assayed resulting one order of magnitude less active than the corresponding E isomer in both AChE and MAO-B inhibition.…”

Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies

“…The evaluation of human serum albumin (HSA) binding for 15 and nonfluorinated congener 22 , for comparative purposes, was performed by surface plasmon resonance (SPR) using warfarin as a reference compound. , Being the most abundant plasma protein, HSA binding can deeply influence drug bioavailability and then plays a central role in the ADME profile of xenobiotics. Indeed, the estimation of HSA affinity can be assessed in the earlier steps of hit discovery.…”

Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease

“…The in vitro inhibitory activities of novel purine nucleosides 5 - 10 , 12 , 13 and 15, and 16 were evaluated against both heterologous (electric eel eeAChE, horse eqBChE) and human (recombinant) cholinesterases isoforms, by applying the Ellmann colorimetric assay, with slight modifications [ 21 , 22 ]. The results are summarized in Table 3 , thus reporting the half maximal inhibitory concentration (IC 50 ) values, or the percent of inhibition at the final tested concentration of 20 μM, with an exception for compounds 15 and 16 , which were tested at 5 μM due to their lower water solubility, but they were not able to produce more than 50% of inhibition for eeAChE and eqBChE.…”