SYNTHESIS AND AChE INHIBITING ACTIVITY OF 2, 4 SUBSTITUTED 6-PHENYL PYRIMIDINES

doi:10.4067/S0717-97072012000300020

Paper

SYNTHESIS AND AChE INHIBITING ACTIVITY OF 2, 4 SUBSTITUTED 6-PHENYL PYRIMIDINES

Published 2012 · Cristian Paz, M. Peter, B. Schmidt

Journal of The Chilean Chemical Society

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Abstract

Novel substituted pyrimidines were synthesized from methyl 2,4-dioxo-4-phenyl-butanoate (I-A) and urea, followed by Mitsunobu coupling of I-A with benzyl or allyl alcohol to give the corresponding 2-hydroxypyrimidine ethers in good yields. Saponification of I-A, followed by reaction with benzyl or allyl amines in the presence of TBTU yielded 2-hydroxy-6-phenyl-pyrimidine 4-carboxamides. AChE and BuChE assays revealed 2-hydroxy-6-phenyl-pyrimidine-4- carboxyallyamide as the most active compound, IC 50 = 90 μM, with no inhibition of BuChE. . Those alterations are associated with regional deficits in the cholinergic system. The development of acetylcholinesterase (AChE) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD 2 and the resultant cholinergic deficit contributes to the cognitive impairment of these patients 3 . Cholinesterase inhibitors (ChEIs) are considered to be valuable as a therapeutic target and they have become the main approach to symptomatic treatment; Donepezil, galantamine and rivastigmine are the first line pharmacotherapy for mild to moderate Alzheimer's disease 4 . The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine increasing the availability of acetylcholine in central synapses 4 (final concentration of 0.03 U/mL and 0.01 U/mL, respectively) were added to each well, and the plates were pre-incubated for 30 min at room temperature. After the pre-incubation period, acetylthiocholine iodide (or butyrylthiocholine iodide) was added to a final concentration of 200 μM. 5,5`-Dithio-bis(2- nitrobenzoic acid) (DTNB) was used for the measurement of cholinesterase activity. The hydrolysis of ACh or BCh was monitored by following the formation of the yellow 5-thio-2-nitrobenzoate anion. The absorbance was read in a Thermo Multiskan Ex Instrument microplate reader at 405 nm after 3 min. The enzyme activity was calculated as a percentage compared to a control using only the buffer and enzyme solution. The compounds were assessed in the dilution interval of 500-15.63 μg/mL, and the alkaloid galanthamine was used as the reference compound. The ChEs inhibitory activity of each compounds was expressed in terms of the IC 50 value (μg/mL and μM required to inhibit the hydrolysis of the substrate by 50%), as calculated from the dose- response curve.

Study Snapshot

2-hydroxy-6-phenyl-pyrimidine-4-carboxamide shows potential as an effective acetylcholinesterase inhibitor for Alzheimer's disease treatment.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

SYNTHESIS AND AChE INHIBITING ACTIVITY OF 2, 4 SUBSTITUTED 6-PHENYL PYRIMIDINES

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References

Drug and Alcohol Dependence

ADHD prevalence in substance use disorder patients varies, with a DSM-5 change potentially affecting this variability and impacting treatment outcomes.

Citations

Design, synthesis and bioevaluation of 2-mercapto-6-phenylpyrimidine-4-carboxylic acid derivatives as potent xanthine oxidase inhibitors.

The designed compounds show submicromolar inhibitory potency, with compound 9b showing the most potent enzyme inhibitory activity.

Enaminonitrile as Building Block in Heterocyclic Synthesis: Synthesis of Novel 4H-Furo[2,3-d][1,3]oxazin-4-one and Furo[2,3-d]pyrimidin-4(3H)-one Derivatives

Enaminonitrile serves as a building block for the synthesis of novel 4H-Furo[2,3-d]pyrimidin-4(3H)-one derivatives and their transformation into various nitrogen nucleophiles.