In Alzheimer’s
disease, neurons slowly degenerate due to
the accumulation of misfolded amyloid β and tau proteins. In
our research, we performed extended studies directed at amyloid β
and tau aggregation inhibition using
in cellulo
(
Escherichia coli
model of protein aggregation),
in silico
, and
in vitro
kinetic studies.
We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional
anti-Alzheimer’s agents and identified very potent dual aggregation
inhibitors. Among the tested derivatives, we selected compound
18
, which exhibited a unique profile of biological activity.
This compound was the most potent and balanced dual aggregation inhibitor
(Aβ
42
inhibition (inh.) 80.0%, tau inh. 68.3% in
10 μM), with previously reported
in vitro
inhibitory
activity against
h
BuChE,
h
BACE1,
and Aβ (
h
BuChE IC
50
= 5.74 μM;
h
BACE1 IC
50
= 41.6 μM; Aβ aggregation
(aggr.) inh. IC
50
= 3.09 μM). In docking studies
for both proteins, we tried to explain the different structural requirements
for the inhibition of Aβ vs tau. Moreover, docking and kinetic
studies showed that compound
18
could inhibit the amyloid
aggregation process at several steps and also displayed disaggregating
properties. These results may help to design the next generations
of dual or selective aggregation inhibitors.
Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β-amyloid (Aβ1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1-42 antiaggregating power (40.3 %).
Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention--compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer's agents.
Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N- and C-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structure-activity relationships and molecular modeling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC of 3.54μM, selectivity MAO-A/MAO-B index of 27.7) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support the suitability of the 4-triazolylalkyl propargylamine scaffold for exploring the design of multipotent anti-Alzheimer compounds endowed with irreversible MAO-B inhibitory activity.
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