Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations.

doi:10.1021/JM00066A003

Paper

Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations.

Published Jul 9, 1993 · K. Scott, I. Edafiogho, Erica L. Richardson

Journal of medicinal chemistry

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91

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0

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Abstract

This report continues the in-depth evaluation of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate , 1 (ADD 196022), and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 2, two potent anticonvulsant enaminones. These compounds were evaluated employing the amygdala kindling model. Neither 1 nor 2 was active against amygdala kindled seizures, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported. Additional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg. Several active analogs have been prepared with the view to minimizing toxicity. In a special ip rat screen developed by the Antiepileptic Drug Development (ADD) Program, these newer analogs were evaluated for protection against maximal electroshock seizures (MES) at 10 mg/kg and neurotoxicity at 100 mg/kg. From this screen, several compounds were shown to be safer alternatives, the most notable was methyl 4-[(p-bromophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 13. Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a protective index (TD50/ED50) of > 67. By variation in the ring size, additional aromatic substitutions and the synthesis of acyclic analogs, these newer compounds provide a more definitive insight into the structure-activity correlation. CLOGP evaluation and molecular modeling studies are also provided to further elaborate the molecular characteristics of potential anticonvulsant enaminones.

Non-RCT

Animal Study

Highly Cited

Study Snapshot

Newer enaminones show potential as safer alternatives for treating epilepsy, with methyl 4-[(p-bromophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate showing the highest protective index.

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 anticonvulsant activity of enaminones. 2. Further structure-activity correlations.

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References

Citations

Molecular docking study and molecular dynamics simulation of ethyl 3,5‐diphenyl‐1H‐pyrrole‐2‐carboxylate and (Z)‐ethyl‐2‐(3‐oxo‐1,3‐diphenylprop‐1‐enylamino)acetate

The synthesized compounds show good drug-like molecules and friendly pharmacokinetics, making them valuable candidates for further structural modification to act as potential inhibitors of AChE and glycosidase enzymes.

Design and development of trifluoromethylated enaminone derivatives as potential anticonvulsants

Compound 7 showed moderate anticonvulsant activity in rodent models, but not as well as previous lead compound THA40, indicating further lead optimization efforts.

Synthesis and structure of regioisomeric amino enones containing 2-pyridyl and CF3 substituents

Regioisomeric amino enones with 2-pyridyl and CF3 substituents show planar molecules and U-shaped configurations, affecting electron density distribution and C-C bond lengths.

Synthesis of N-Alkyl Enamino Ketones Based on 3-Acyl-4H-polyfluorochromen-4-ones and Their Antimicrobial Activity

N-hexyl and N-octyl derivatives of 3-acetyl-4H-polyfluorochromen-4-ones show promising antimicrobial activity against fungi and bacteria.

Facile, regioselective oxidative selenocyanation of N-aryl enaminones under transition-metal-free conditions

This study demonstrates a facile, regioselective oxidative selenocyanation of N-aryl enaminones under transition-metal-free conditions, leading to the synthesis of selenocyanated chromones, indoles, and anilines

Palladium Catalyzed Insertion Reaction of Isocyanides with 3-Arylisoxazol-5(4H)-ones: Synthesis of 4-Aminomethylidene Isoxazolone Derivates.

This study presents a new palladium-catalyzed method for the synthesis of 4-aminomethylidene isoxazolone derivatives, preserving the ring structure while involving only the C-H bond of the methylene group.

Metal-free, green and efficient oxidative α halogenation of enaminones by halo acid and DMSO

This metal-free, green, and efficient oxidative halogenation of N-aryl enaminones using DMSO and halo acid provides excellent yields for the synthesis of chromenone derivatives.