Azolylchromans as a novel scaffold for anticonvulsant activity Saeed Emami, a, * Abbas Kebriaeezadeh, b Mohammad Jafar Zamani b and Abbas Shafiee c a Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran b Department of Toxicology and Pharmacology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran c Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran Received 29 November 2005; revised 19 December 2005; accepted 5 January 2006 Available online 24 January 2006 Abstract—A series of azolylchroman derivatives were prepared as conformationally constrained analogs of (arylalkyl)azole anticon- vulsants. The anticonvulsant activities of the compounds were evaluated by determining seizure latency and protective effect against pentylenetetrazole (PTZ)-induced lethal convulsions in mice at a dose of 5 mg/kg. Among these compounds, 7-chloro-3-(1H-imi- dazol-1-yl)chroman-4-one and 3-(1H-1,2,4-triazol-1-yl)chroman-4-one exhibited significant action in delaying seizures as well as effective protection against PTZ-induced seizures and deaths. Ó 2006 Elsevier Ltd. All rights reserved. Epilepsy is a major neurological disorder and up to 5% of the world population develop epilepsy in their life- time. 1 It is a chronic and often progressive disorder characterized by recurrent transient attacks which are caused by an abnormal discharge of cerebral neurons. 2,3 However, with the available antiepileptic drugs on the market, about 70% of the people with epilepsy achieve satisfactory seizure control and approximately 30% of patients are refractory to first-line antiepileptic drugs. Furthermore, even though ten new antiepileptic drugs have been licensed for clinical use during the last decade, these drugs have had little impact on the prognosis of intractable epilepsy. Consequently, the chances of sei- zure freedom with monotherapy for these patients are low, and invariably they are prescribed polytherapy in an attempt to enhance seizure control. 2,4 There is continuing demand for new anticonvulsant agents, as it has not been possible to control every kind of seizure with the currently available antiepileptic drugs. More- over, the current therapy of epilepsy with modern anti- epileptic drugs is associated with side effects, dose- related and chronic toxicity, and teratogenic effects. 4,5 Therefore, the development of new antiepileptic agents with approved therapeutic properties is still popular. 2,4,6 One of the structurally distinct classes of antiepileptic drugs is the (arylalkyl)azoles. In recent years, loreclezole 1 has emerged as a structurally novel 1,2,4-triazole anti- convulsant with broad-spectrum activity. Loreclezole potentiates GABA A receptor-mediated Cl À currents through a site present on the b2 and b3 (but not b1) sub- units of GABA A receptors. 7,8 Furthermore, several 1,2,4- triazole derivatives have been proven to exhibit anticon- vulsant properties. 9–12 Another structure among the azoles that were studied for anticonvulsant activity is imidazole nucleus. Nafimidone 2 and denzimole 3 are the examples of imidazole analogs, which possess a profile of activity similar to that of phenytoin or carbamazepine but distinct from those of barbiturates or valproic acid. 13–16 In addition, certain azolylchromanone derivatives were synthesized in our laboratory, as intermediates for achieving some antifungal agents. 17–19 These compounds can be considered as conformationally constrained analogs of (arylalkyl)azoles (loreclezole 1, nafimidone 2, and denzimole 3)(Fig. 1) and consist of a chroman ring that, in itself, shows some anticonvul- sant activity. 20,21 In view of the above observations, the preparation of azolylchromanone derivatives 4, and related compounds 5 and 6 was aimed at investigating anticonvulsant activ- ity (Table 1). As illustrated in Scheme 1, 3-azolylchroman-4-ones 4 were obtained from 2 0 -hydroxy-2-azolylacetophenones 7 according to the method reported in the literature. 17–19 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.01.004 Keywords: Anticonvulsant; Azole; Chroman. * Corresponding author. E-mail: sd_emami@yahoo.com Bioorganic & Medicinal Chemistry Letters 16 (2006) 1803–1806