Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

Abstract

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1-40 , Aβ1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.

Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases

“…Contilisant showed improved irreversible inhibition of MAOB compared to ASS234, which prefers MAOA.T he affinities for binding at human H3R as the target and H4R, the structurally most homologous G-protein-coupled receptor, as an off-target were measured ( Table 1). Ab [25][26][27][28][29][30][31][32][33][34][35] ), comparable to that offered by melatonin ( Figure 2). Surprisingly,A SS234 showed remarkable affinity at H3R, but the highest affinity was found for 2 and contilisant, which both contain the propyloxy linker connected to pyrrolidine and piperidine moieties,r espectively.G ood affinities were also found for 6,c ontaining ar elated H3R pharmacophore,and 7,which lacks the propargylamine group but features the propyloxy linker.C ompounds with ethyloxy or pentyloxy spacers showed moderate H3R affinities.T hese findings confirmed previously obtained SAR results for H3R antagonists.…”

Design, Synthesis and Biological Evaluation of Potent Antioxidant 1‐(2,5‐Dimethoxybenzyl)‐4‐arylpiperazines and N‐Azolyl Substituted 2‐(4‐Arylpiperazin‐1‐yl)

“…As presented in Tables 3 and 4, the ORAC values for compounds in the different chemical series ranged from 4.98 to 9.10 in series I , from 2.14 to 7.89 in series II , and from 2.96 to 9.42 in series III . Accordingly, compared to ferulic acid, the antioxidant reference standard with an ORAC value of 3.74 Trolox equivalents (TE), all compounds showed a strong capacity to scavenge a peroxyl radical.…”

“…Within this series, incorporation of either electron‐donating or electron‐withdrawing substituents at position C4’ resulted in compounds with significantly less antioxidant power ( 2 , 3 , 4–8 ). In fact, 1‐(2,5‐dimethoxybenzyl)‐4‐arylpiperazines ( 1 ), with an impressive TE value of 9.10, is the second most potent antioxidant agent found among all compounds tested, 2.4 times more potent than ferulic acid . In this respect, comparing the TE values for compounds 4–8 , it is observed that the stronger the electron‐withdrawing capacity of the substituent, the lower the antioxidant power of the compound.…”

Multipotente Liganden mit kombinierter Cholinesterase‐ und Monoaminooxidase‐Inhibition sowie Histamin‐H3R‐Antagonismus bei neurodegenerativen Erkrankungen

“…Erwähnenswert bezüglich der molekularen Eigenschaften von Contilisant, erhoben mit molsoft, [26] ist die hçhere Hydrophilie (MolLogP = 3.7) im Vergleich zu ASS234 (MolLogP = 5.5), was einen verbesserten Wirkstoff-¾hnlichkeitsfaktor bestätigt. [28] Die neuroprotektiven Fähigkeiten wurden anhand dreier unterschiedlicher Toxizitätsmechanismen untersucht, die bei Morbus Alzheimer an neurodegenerativen Prozessen beteiligt sind: [29] nicht aktiv [25] nicht aktiv [25] Deprenyl nicht aktiv [25] nicht aktiv [25] Donepezil [4] Eine potenzielle Verbesserung der Erinnerungs-und Lernfähigkeit in vivo durch ASS234 und Contilisant wurde mittels "Novel-Object-Recognition"(NOR)-Test in Mäusen (Abbildung 3) untersucht, [30] vor und nach Gabe von Lipopolysaccharid (LPS), das eine signifikante Reduktion der NOR-Leistung verursacht. Die Ergebnisse zeigen die Fähigkeit von Contilisant und ASS234, die Blut-Hirn-Schranke mittels passiver Diffusion zu überwinden.…”

“…Die antioxidative Kapazitätd er Hybride 1-5 und 7 wurde mittels "Oxygen-Radical-Absorbance-Capacity"(ORAC-FL)-Test gemessen (Tabelle 1), [27] wobei alle MTLs gute Radikalfänger-Eigenschaften zeigten und Contilisant ähnliche Werte erzielte wie die Positivkontrolle Ferulasäure (3.74 AE 0.22 TE). [28] Die neuroprotektiven Fähigkeiten wurden anhand dreier unterschiedlicher Toxizitätsmechanismen untersucht, die bei Morbus Alzheimer an neurodegenerativen Prozessen beteiligt sind: [29] nicht aktiv [25] nicht aktiv [25] Deprenyl 0 30…”