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KMID : 1059520100540010158
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Journal of the Korean Chemical Society
2010 Volume.54 No. 1 p.158 ~ p.164
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Synthesis of Novel 2,5-Disubstituted 1,3,4-Thiadiazoles:Structural Requirements Necessary for Anticonvulsant Activity
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Harish Rajak
Navneet Aggarwal
Sushil Kashaw
Murli Dhar Kharya
Pradeep Mishra
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Abstract
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Epilepsy, a common neurological disorder characterized by the periodic sudden loss or impairment of consciousness, often followed by convulsions. Approximately 60 million people worldwide suffer from epilepsy, making this condition the
second leading neurological disorder.1 Epilepsy also affects about 4% of individuals over their lifetime. Despite the development of several new anticonvulsants, about one third of patients fail to experience seizure control and other do so only at the expense of significant dose-related toxicity and peculiar adverse effects.2 Thus there is an enormous need for the development of more effective and safer antiepileptic drug. In the last two decades, aryl semicarbazones has been identified and established as a structurally novel class of compounds with remarkable anticonvulsant activity.3-5 On the other hand, several investigations have revealed that 1,3,4-thiadiazole analogues possess considerable anticonvulsant activity.6-8 A general model for anticonvulsant activity has been proposed as a result of the conformational studies of the clinically active anticonvulsant drugs such as phenytoin, carbamazepine, lamotrigine, rufinamide and phenobarbitone9,10 These semicarbazones based pharmacophore models are consist of following four essential binding sites: (i) An aryl hydrophobic binding site (A) with halo substituent preferably at para position; (ii) A hydrogen bonding domain (HBD); (iii) An electron donor group (D) and (iv) Another hydrophobic-hydrophilic site controlling the pharmacokinetic properties of the anticonvulsant (C) (Fig.1). In earlier studies on pharmacophore model, our research group confirmed that the presence of aryl group (preferably halogen substituted) near the semicarbazone moiety is one of the indispensable parameters for anticonvulsant activity.
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KEYWORD
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1,3,4-Thiadiazoles, Semicarbazones, Anticonvulsant activity
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