Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease

Chioua, Mourad; Buzzi, Eleonora; Moraleda, Ignacio; Iriepa, Isabel; Maj, Maciej; Wnorowski, Artur; Giovannini, Catia; Tramarin, Anna; Portali, Federica; Ismaïli, Lhassane; López‐Alvarado, Pilar; Bolognesi, María Laura; Menéndez, J. Carlos; Marco‐Contelles, José; Bartolini, Manuela

doi:10.1016/j.ejmech.2018.06.044

Cited by 44 publications

(42 citation statements)

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“…Ca +2 channel blockade capacity of compounds 3a-p, compared to nimodipine as standard, has been carried out following the usual methodology [ 12 , 13 , 25 ]. The new compounds showed a good inhibition percentage of calcium flux ranging from 18.58 (3a) to 80.19 (3o).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca+2 channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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“…Tacripyrimidines is the trivial name given by the authors to the 5‐amino‐4‐aryl‐3,4,6,7,8,9‐hexahydropyrimido[4,5‐b]quinoline‐2(1 H )‐thiones, which were recently designed by juxtaposition of tacrine and 3,4‐dihydropyrimidin‐2(1 H )‐thiones . The authors designed these new hybrids to achieve compounds with a more balanced activity towards both ChEs and Ca 2+ channels.…”

Section: Tacripyrimidinesmentioning

confidence: 99%

“…Tacripyrimidines is the trivial name given by the authors to the 5-amino-4-aryl-3,4,6,7,8,9-hexahydropyrimido[4,5-b] quinoline-2(1H)-thiones, which were recently designed by juxtaposition of tacrine and 3,4-dihydropyrimidin-2(1H)thiones. [26] The authors designed these new hybrids to achieve compounds with a more balanced activity towards both ChEs and Ca 2 + channels. As in the previous attempts, the tacrine scaffold was used as template for ChE inhibition while the 3,4-dihydropyrimidin-2(1H)-thione fragment (Figure 7) was selected on the basis of the well known capacity of 3,4dihydropyrimidin-2(1H)-thiones to act not only as good CCB, [36,37] but also as neuroprotective agents toward Abinduced toxicity, likely by attenuating the metal-mediated toxicity of Ab.…”

Section: Tacripyrimidinesmentioning

confidence: 99%

“…In previous accounts [11][12][13] dedicated to our contributions to this topic, we have reviewed the work and results on: (a) pyranotacrines of type (I) (Figure 1), and identified the hittacrine ethyl 5-amino-4-(4-methoxyphenyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano [2,3-b]quinoline-3-carboxylate (2, Figure 1) a potent VDCC blocking compound (blocking the K + -induced Ca 2 + entry by 49.7 %), potent reversible, non-competitive AChEI (IC 50 = 0.87 AE 0.40 mM), showing also a moderate BuChE inhibition (IC 50 = 6.2 AE 0.6 mM); [11] (b) (benzo)chromenopyranotacrines of type (II) (Figure 1), the most relevant tacrine in this series being 14-(3,4dimethoxyphenyl)-9,11,12,14-tetrahydro-10H-benzo [5,6] chromeno [2,3-b]quinolin-13-amine (3), a mixed-type, selective human AChEI (hAChEI) (IC 50 = 0.083 AE 0.024 mM), less toxic than tacrine, and endowed with neuroprotective activity (Figure 2), [12] and (c) pyridotacrines (III) (Figure 1), whose most attractive tacrine analogue was pyridotacrine (4) ( Figure 1) which acted as a submicromolar inhibitor of hAChE (0.78 AE 0.08 mM) and a micromolar inhibtor of equine BuChE (12 AE 1 mM) and was able to significantly mitigate the reduction of cell viability (SH-SY5Y cell line) upon exposure to okadaic acid, a known inhibitor of the enzyme phosphoprotein phosphatase 2A, which is the main dephosphorylating enzyme of the tau protein. [13] The present account focuses on the review of the achievements related to tacripyrines (IV, Figure 2), which are compounds resulting from the hybridization oftacrine and 1,4-dihydropyridine (1,4-DHP) scaffold, [14][15][16][17][18][19][20][21][22][23][24][25] pyrimidotacripyrines (V, Figure 2), [26] and related simplified annulated tacrines, such as the hupertacrines (VI, Figure 2)...…”

Section: Introductionmentioning

confidence: 99%

“…Structure and retrosynthetic analysis of tacripyrimidines [26]. Structure of HuperTacrines, (À)-huperzine A and tacrine.P e r s o n a l A c c o u n t T H E C H E M I C A L R E C O R D Chem.…”

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Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines

Bartolini

Marco‐Contelles

2018

The Chemical Record

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Notwithstanding the clinical use of tacrine was hampered by severe hepatotoxicity, tacrine still remains a reference scaffold in the search for new efficient drugs for Alzheimer's disease therapy. In this account we summarize the efforts toward the development and characterization of non‐hepatotoxic tacripyrines and related tacrine analogues resulting from the substitution of the benzene ring by a 1,4‐dihydropyridine, a 1,2,3,4‐tetrahydropyrimidine or a pyridone nucleus. These efforts have successfully led to the identification of a number of promising hits endowed with interesting multifunctional profiles. These include the 4′‐metoxytacripyrine (S)‐ITH122, able to target cholinesterases (ChEs), beta‐amyloid (Aβ) and Ca2+ channels, the racemic 3′‐methoxytacripyrimidine EB65F2, the first fully balanced micromolar inhibitor of ChEs and Ca2+ channels, and tacripyrine (−)‐SCR1693 a GSK‐3β (enzyme involved in tau phosphorylation) inhibitor able to also lower Aβ production in N2a cells.

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Design, Synthesis, and Molecular Docking of Some Novel Tacrine Based Cyclopentapyranopyridine‐ and Tetrahydropyranoquinoline‐Kojic Acid Derivatives as Anti‐Acetylcholinesterase Agents

Babaee

Chehardoli

Akbarzadeh

et al. 2021

Chemistry & Biodiversity

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A novel series of tacrine based cyclopentapyranopyridine‐ and tetrahydropyranoquinoline‐kojic acid derivatives were designed, synthesized, and evaluated as anti‐cholinesterase agents. The chemical structures of all target compounds were characterized by 1H‐NMR, 13C‐NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC50 values of 4.18–48.71 μM rather than butyrylcholinesterase enzyme (BChE) with IC50 values of >100 μM. Among them, cyclopentapyranopyridine‐kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline‐kojic acid. The compound 10‐amino‐2‐(hydroxymethyl)‐11‐(4‐isopropylphenyl)‐7,8,9,11‐tetrahydro‐4H‐cyclopenta[b]pyrano[2′,3′ : 5,6]pyrano[3,2‐e]pyridin‐4‐one (6f) bearing 4‐isopropylphenyl moiety and cyclopentane ring exhibited the highest anti‐AChE activity with IC50 value of 4.18 μM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H2O2‐induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug‐likeness for the compound 6f. Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.

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Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease

Cited by 44 publications

References 49 publications

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines

Design, Synthesis, and Molecular Docking of Some Novel Tacrine Based Cyclopentapyranopyridine‐ and Tetrahydropyranoquinoline‐Kojic Acid Derivatives as Anti‐Acetylcholinesterase Agents

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