European Journal of Medicinal Chemistry 37 (2002) 231 – 236 Original article Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones Perumal Yogeeswari a, *, Dharmarajan Sriram a , Logantha Ramamoorthy Jeewanlal Sunil Jit a , Sathiyanesan Sathish Kumar a , James P. Stables b a Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani 333 031, India b Preclinical Pharmacology Section, Epilepsy Branch, National Institute of Health, Bethesda, MD 20892 -9020, USA Received 6 November 2001; received in revised form 16 January 2002; accepted 17 January 2002 Abstract Ten 6-chlorobenzothiazolyl-2-thiosemicarbazones were synthesised and screened for anticonvulsant and neurotoxic properties. Most of the compounds showed anticonvulsant activity against both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole screens. Eight compounds have shown good protection in the rat p.o. MES test at 30 mg kg -1 . Compound 1 [4-(6-chlorobenzothiazol-2-yl)-1-(3-isatinimino)thiosemicarbazone] emerged as the most promising one with an ED 50 of 17.86 and 6.07 mg kg -1 in mice i.p. and rat p.o., respectively. Compound 1 showed a weak ability to block the expression of fully kindled seizures. © 2002 Published by E ´ ditions scientifiques et me ´dicales Elsevier SAS. Keywords: Benzothiazolylthiosemicarbazones; Electroshock; Pentylenetetrazole; Neurotoxicity; Fully kindled www.elsevier.com/locate/ejmech 1. Introduction The conditions grouped under the term epilepsy cons- titute an area of continuing medical need. It has been estimated that about 20% of the patients with epilepsy using the first generation of antiepileptic drugs (Pheno- barbital, Phenytoin, Carbamazepine, Sodium valproate and Diazepam) were not able to acquire adequate control of seizure [1]. In recent years, aryl semicarba- zones have emerged as structurally novel anticonvul- sants [2 – 4]. The aryl semicarbazones were believed to interact at locations on the putative binding site desi- gnated as aryl binding site, a hydrogen bonding domain and an auxiliary aryl binding site [5]. The aryl group can be replaced by other hydrophobic moieties with retention of anticonvulsant activity [6]. In 1985, Rilu- zole [6-(trifluoromethoxy)-2-benzothiazolamine] was re- ported to be a potent anticonvulsant agent [7]. Various 2-benzothiazolamine derivatives were investigated as anticonvulsants and the 6-chloro compound possessed anticonvulsant activity in MES with no ataxia [8]. In our earlier report thiosemicarbazone derivatives have shown moderate anticonvulsant activity [9]. Thus in the present study 6-chlorobenzothiazolyl thiosemicarba- zones, bioisoster of semicarbazones have been synthe- sised to understand their potential as anticonvulsants. Isatin derivatives were reported to possess anticonvul- sant properties [3,9 – 11], and hence considered impor- tant in the present study to investigate the effect of the auxiliary heteroaryl ring. Epilepsy, particularly tempo- ral lobe epilepsy with complex partial seizures, is often associated with disturbance of cognitive function and behaviour, and it has been suggested that a drug combining cognition enhancing and antiepileptic acti- vity would be a benefit in the treatment of epileptic patients [12]. In the present study one compound has been tested in the preliminary hippocampal-kindling screen. The 6-chlorobenzothiazolyl thiosemicarbazones have shown activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) screens, which would serve as structurally novel class for subsequent molecular modifications. * Corresponding author. Tel.: +91-15976-44684; fax: +91-15976- 44183. E-mail address: pyogie – 2000@rediffmail.com (P. Yogeeswari). 0223-5234/02/$ - see front matter © 2002 Published by E ´ ditions scientifiques et me ´dicales Elsevier SAS. PII:S0223-5234(02)01338-7