Structure–activity relationship of phenytoinergic antiepileptic drugs related to ameltolide

Abstract

Ameltolide shares with phenytoin and carbamazepine a common mode of action involving interaction with central voltage-dependent sodium channels. Ameltolide and structurally related benzanilides were subjected to molecular modeling studies using both molecular mechanics (MM2, Amber96, and OPLS) and semiempirical quantum mechanics (AM1, PM3, and PM3 Cosmo) to resolve a paradox: while compounds with a phenytoin-like pharmacological profile possess a CO-NH moiety in a cis-configuration, ameltolide was found via X-ray crystallography to exist in the trans-configuration. Results obtained both by molecular mechanics and semiempirical methods indicate that for ameltolide, the cis and trans forms have similar energy content. Additional ab initio calculations performed at 6-31G** gave a DE (Z -E) on the order of 3 kcal/mol. In view of this small energy difference between the cis and trans forms, it is conceivable that these benzanilides bind to their biological target in their cis configuration, therefore assuming a common structure-activity relationship with classical antiepileptic agents.

Molecular docking analysis and molecular dynamics simulation study of ameltolide analogous as a sodium channel blocker

“…25−28 X-ray crystallography revealed that ameltolide exists in the trans configuration but using molecular modeling it was suggested that the CO-NH moiety of ameltolide and its derivatives bind to their biological target in their cis configuration. 29 Because of the greater reliability of the crystallographic results and small energy difference between the cis and trans forms (3 kcal/mol), 29 in the flexible docking study the trans form was considered and also the amide bond was considered as a rotatable bond to create both the cis and trans forms in docking calculations. The chemical structures of inhibitors (Figure 1) were constructed using HyperChem software (version 7, Hypercube Inc.).…”

“…Because of the greater reliability of the crystallographic results and small energy difference between the cis and trans forms (3 kcal/mol), 29 in the flexible docking study the trans form was considered and also the amide bond was considered as a rotatable bond to create both the cis and trans forms in docking calculations. The chemical structures of inhibitors ( Figure 1) were constructed using HyperChem software (version 7, Hypercube Inc.).…”

Synthesis and Antiepileptic Activity Assessment of 5-Benzoyloxindole, a Novel Phenytoinergic Template

“…To our point of view, modification of these leads aiming at diminishing electron-density around the aromatic rings was considered as an important structural feature. Compounds such as ameltolide (4) [10][11][12] or their phthalimide analogues are flanked by an amino electrodonating group and therefore do not meet our structural stringent requirement. As a proof of concept, let us consider that ameltolide was stopped in preclinical developments due to toxicity (lung fibrosis) in animal species.…”