European Journal of Pharmaceutical Sciences 26 (2005) 97–103 Synthesis and biological evaluation of new N-substituted-N ′ -(3,5- di/1,3,5-trimethylpyrazole-4-yl)thiourea/urea derivatives Bedia Koc ¸yi˘ git Kaymakc ¸ıo˘ glu a , Sevim Rollas a,∗ , Eylem K ¨ orce˘ gez b , Feyza Arıcıo˘ glu b a Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpa¸ sa, 81010 Istanbul, Turkey b Marmara University, Faculty of Pharmacy, Department of Pharmacology, Haydarpa¸ sa, 81010 Istanbul, Turkey Received 6 May 2004; received in revised form 4 January 2005; accepted 9 May 2005 Available online 28 June 2005 Abstract Several thiourea and urea derivatives were prepared by the reaction of 4-aminopyrazoles with substituted isothiocyanates or isocyanates. The novel compounds were tested anticonvulsant activity using by pentylenetetrazole-induced seizure (PTZ) and maximal electroshock seizure (MES) tests. Among the tested compounds, thiourea derivatives of 4b were afforded 90 and 100% protection in PTZ and MES tests at 50mg/kg, respectively. Urea derivatives of 5a and 5b were afforded 82 and 100% protection both at 25 and 50 mg/kg. Also synthesized compounds were screened for antituberculosis activity against Mycobacterium tuberculosis H 37 Rv at 6.25 g/mL concentration but they were not found active at these concentration. In addition, some selected compounds were evaluated for in vitro anti-HIV activity and they were all negative. © 2005 Elsevier B.V. All rights reserved. Keywords: Anticonvulsant activity; 3,5-Dimethylpyrazole; Thiourea; Urea 1. Introduction Epilepsy is characterized by seizures, which are due to abrupt discharge of a large population of neurons firing synchronously. It is estimated that in developed countries 0.5–1% of the population suffer from epilepsy. However, with the available antiepileptic drugs on the market, about 70% of the people with epilepsy achieve satisfactory seizure control. During the 5 years, several new drugs have been approved or in the process of being approved, e.g. lamotrig- ine, gabapentin, tiagabine and milacemide. Although these drugs have been shown to be effective in reducing seizures in a number of patients their efficacy does not appear to be superior to that of the drugs developed earlier. For that rea- son, the need for more effective and less toxic antiepileptic drugs still exists (L¨ oscher et al., 1991). In recent years, urea and thioureas (Heinisch et al., 1997; Masereel et al., 1997; Pandeya et al., 2001) have emerged ∗ Corresponding author. Tel.: +90 216 414 2962; fax: +90 216 345 2952. E-mail address: sevim@sevimrollas.com (S. Rollas). as structurally novel anticonvulsant. The anticonvulsant drug design was based on the presumption (Pandeya et al., 1998) that for the activity in maximal electroshock (MES) evalu- ation at least one phenyl or similar aromatic group in close proximity to two electron donor atoms and for activity in the pentylenetetrazole (PTZ) evaluation an alkyl group substi- tuted close to two electron donor atoms was required. It has been hypothesized that, ureas and thioureas displaying anti- convulsant activity interact at locations on the putative bind- ing site designated as aryl binding site, a hydrogen bonding domain and an auxiliary aryl or other hydrophobic binding site (Dimmock et al., 2000). In view of these data, thiourea moities have been attached to a pyrazole ring and to an aryl or alkyl group. Thus, the aim of the present study was to prepare a series of thiourea and ureas and evaluated for anticonvulsant properties using MES and PTZ tests in mice. In addition to anticonvulsant activity, similar compounds containing thiourea moiety have shown antituberculosis (K¨ uc ¸¨ ukg¨ uzel et al., 2001) and anti-HIV (Bell et al., 1995; Uc ¸kun et al., 1999) activities. Therefore, all synthesized com- pounds were screened for antituberculosis activity and some 0928-0987/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2005.05.005