Full Paper Design of Benzothiazole-1,3,4-thiadiazole Conjugates: Synthesis and Anticonvulsant Evaluation Nadeem Siddiqui, Priya Ahuja, Sachin Malik, and Satish K. Arya Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard, Hamdard Nagar, New Delhi, India Various 2-[(6-substituted-1,3-benzothiazol-2-yl)amino]-N-[5-substituted-phenyl-1,3,4-thiadiazol-2-yl]acet- amides were synthesized with a prospective exploration of “lead hopping”, using pharmacophoric elements for in vivo anticonvulsant activity. This yielded three potent candidates (5i, 5t, and 5u) in the preliminary screening employing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) test, showing minimal neurotoxicity. Their quantitative study indicated an increase of nearly 2–10 times for the MES test and 7- to 67-fold for the scPTZ test in the protective index, the keystone in drug discovery for anticonvulsant activity. Keywords: Anticonvulsants / Benzothiazole / Neurotoxicity / Phenytoin / Thiadiazole Received: March 7, 2013; Revised: July 22, 2013; Accepted: July 26, 2013 DOI 10.1002/ardp.201300083 Introduction Epilepsy is one of the common chronic diseases affecting 0.5– 1% of the population worldwide. It ranks as the third most frequent neurological disorder, after cerebrovascular disease and dementia [1]. According to the International League against Epilepsy and the International Bureau of Epilepsy, epilepsy is the disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social con- sequences of the condition [2]. Current antiepileptic drugs are effective in controlling seizures in about 70% of the patients, but their use is often limited by side effects [3]. About one-third of the patients do not respond well to the currently available treatments, even if multiple drugs with complementary activities are used [4]. Over the last decades, the optimum therapy for seizures manifests complete control of seizures, absence of bother- some side effects, and an emphasis on maximizing quality of life. In spite of the concerted attempts by the physicians to utilize the available pharmacotherapies to their full advan- tage, the prospect of freedom from seizures and adverse effects remains elusive for a considerable number of epileptic patients. Approximately 25–30% of patients continue to suffer from seizures despite state-of-the-art treatment [5]. One example of a rationally designed anticonvulsant agent having an aminoacetamide linkage is the phase III drug brivaracetam, chemically 2-(2-oxo-4-propyl-pyrrolidin-1-yl)- butamide. It is an agonist of the synaptic vesicle protein SV2A and an alkylation hybrid of valproic acid and levetiracetam, an anticonvulsant drug made by UCB Pharma (Fig. 1). Moreover, the presynaptic N-methyl-D-aspartate (NMDA) glutamate receptor antagonist rilutek (riluzole), a 2-aminobenzothiazole analog generated by Rhone-Poulenc Rover, Inc. Collegeville (PA, USA) and marketed by Sanofi- Aventis (chemically, 6-(trifluoromethoxy)benzo[d]thiazol-2- amine), contributed to the designing of the synthesized compounds. The Food and Drug Administration (FDA) granted brivaracetam orphan drug designation for the treatment of symptomatic myoclonus in November 2005. The European Medicines Agency (EMA) granted orphan drug designation to brivaracetam for the treatment of progressive myoclonic epilepsies in August 2005. In December 2010, a phase III trial was initiated for partial-onset seizures [6]. A chemical drawing of the new targeted compounds, as rationally designed through brivaracetam along with riluzole, is represented in Fig. 1. For over a century, despite the refined and efficient methods accrued for the synthesis of thiadiazole, a five- membered aromatic system having three heteroatoms at symmetrical positions has been studied extensively, owing to Correspondence: Nadeem Siddiqui, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard, Hamdard Nagar 110062, New Delhi, India. E-mail: nadeems005@gmail.com Fax: þ91 11 26059688 ext: 5307 Arch. Pharm. Chem. Life Sci. 2013, 346, 819–831 819 ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim