Original article Synthesis of some urea and thiourea derivatives of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidine and their antagonistic effects on haloperidol-induced catalepsy and oxidative stress in mice Faizul Azam a, * , Ismail A. Alkskas a , Musa A. Ahmed b a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Seventh October, P.O. Box 2873, Misurata, Libya b Department of Medicinal Chemistry, Faculty of Pharmacy, Al-Arab Medical University, Benghazi, Libya article info Article history: Received 30 August 2008 Received in revised form 24 March 2009 Accepted 2 April 2009 Available online 14 April 2009 Keywords: Parkinson’s disease Thiazolopyrimidine Urea Thiourea Neuroprotection abstract A series of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7-yl urea and thiourea deriva- tives were designed and synthesized. All the compounds have been evaluated for their antiparkinsonian activity in catalepsy induced by haloperidol in mice. A majority of the compounds exhibited significant antiparkinsonian activity after intraperitoneal administration. The most active compound carries methoxy group at 2-position of the phenyl ring. Some of the potent compounds were selected for biochemical estimations of malondialdehyde, glutathione, superoxide dismutase and glutathione peroxidase from brain homogenate to highlight the neuroprotective properties associated with them. The results obtained in the present study may lead to the development of a suitable approach to the treatment of Parkinson’s disease and may be the starting point for the future drug design. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction Parkinson’s disease (PD) is considered as one of the major progressive neurologic disorders of the elderly population and about three percent of this age group over 65 years have developed the overt illness [1]. Clinically, PD is characterized by the tetrad of tremor at rest, slowness of voluntary movements, rigidity, and postural instability [2]. The cardinal biochemical abnormality in PD is the profound deficit in brain dopamine level, primarily attributed to the loss of neurons of the nigrostriatal dopaminergic pathway [3]. Over the last two decades, tremendous strides toward acquiring a better knowledge of both the etiology and the pathogenesis of PD revealed the free radical theory as one of the mechanisms involved in the pathogenesis of this disease [4]. There is substantial evidence that the brain, which consumes large amounts of oxygen, is particularly vulnerable to oxidative damage. Free radicals are normal products of cellular metabolism [5]. The predominant cellular free radicals are the superoxide (O 2  ) and hydroxyl (OH  ) species [4,6]. Other molecules, such as hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO  ), although not themselves free radicals, can lead to the generation of free radicals through various chemical reactions. Thus H 2 O 2 , in the presence of reduced metal, forms the highly reactive OH  via the Fenton reaction [6]. ONOO  , formed by the reaction of nitric oxide (NO  ) with O 2  , is a highly reactive molecule that also breaks down to form OH  . Together, these molecules are referred to as reactive oxygen species (ROS) to signify their ability to lead to oxidative changes within the cell [6]. Problems occur when the production of ROS exceeds the ability of cells to defend themselves against these substances. This imbalance between cellular production of ROS and the ability of cells to defend themselves against them is referred to as oxidative stress [6]. Oxidative stress can cause cellular damage and ROS oxidize critical cellular components such as membrane lipids, proteins, and DNA, thereby inducing apoptosis or necrosis [7,8]. There is a large scientific literature regarding the relation between ROS production, the induction of apoptosis or necrosis and the pathogenesis of PD [9,10]. Superoxide dismutase (SOD) and glutathione peroxidase (GSH- Px) are among the major antioxidant enzymes present in the * Corresponding author. Tel.: þ218 92 7677641/þ218 91 3300265; fax: þ218 51 628149. E-mail addresses: azamfaizul@yahoo.co.in, faizulazam@gmail.com (F. Azam). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.04.007 European Journal of Medicinal Chemistry 44 (2009) 3889–3897