Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol

Abstract

A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylalkyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone. This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50's = 25 and 56 mg/kg, respectively) and considerably less toxic in the rat (po LD50's = 4550 and 504 mg/kg, respectively). The tertiary alcohol alpha-(9H-fluoren-2-yl)-alpha-methyl-1H-imidazole-1-ethanol was as potent as denzimol in mice (po ED50's = 10 and 12 mg/kg, respectively). This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent antielectroshock activity, little or not activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. All active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450. The SAR's for the anticonvulsant activity and the sleeping time potentiation were similar. The propensity of these (arylalkyl)imidazole anticonvulsants to interact strongly with cytochrome P-450 and thereby impair the metabolism of other antiepileptic drugs may severely limit their clinical utility as anticonvulsants.

Synthesis of Some Oxime Ether Derivatives of 1‐(2‐Naphthyl)‐2‐(1,2,4‐triazol‐1‐yl)ethanone and Their Anticonvulsant and Antimicrobial Activities

“…Compounds with small alkyl groups such as methyl, ethyl, propyl, allyl were active in l100 mg kg -1 dose levels whereas larger groups such as benzyl and substituted benzyl molecules resulted in a lack of anticonvulsant activity and a decrease in toxicity. Although it has been reported in the literature that the activity of nafimidone and denzimol, as well as the other (arylalkyl)imidazoles, are highly MES specific in mice, most of the active compounds 2-6 exhibited activity against both MES and scMet induced seizures [5,8]. This data is in accordance with our previous studies [9,10].…”

Recent Progress in Anticonvulsant Drug Research: Strategies for Anticonvulsant Drug Development and Applications of Antiepileptic Drugs for Non-Epileptic Central Nervous System Disorders

“…Many aryl groups were examined by different research groups and it was found that naphthalene, 4-phenylethylbenzen and fluoren rings as aryl groups showed the highest activities among them [128,129,132]. Walker et al [128] found that 2-substituted naphthalene derivatives were more active than 1-substituted derivatives.…”

Synthesis and Anticonvulsant Activity of O-alkylated Derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone Oxime

“…General procedure for synthesis of O -alkylated derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime (6)(7)(8)(9)(10)(11) and their oxalate salts Appropriate dialkylaminoethyl chloride hydrochloride (1.75 mmol) [methyl chloroacetate (11 mmol) for compound 10 and 1-bromo-3-chloropropane (9 mmol) for compound 11 ] and potassium hydroxide (3.57 mmol, 0.2 g) were added to a hot stirred suspension of compound 5 (0.25 g, 0.9 mmol) in ethyl methyl ketone (45 ml) containing anhydrous potassium carbonate (0.7 g, 5.06 mmol). The reaction mixture was refl uxed for 8 h with continuous stirring.…”