Structure-based design, synthesis, and molecular modeling studies of 1-(benzo[d]thiazol-2-yl)-3-(substituted aryl)urea derivatives as novel anti-Parkinsonian agents

Abstract

1-(Benzo[d]thiazol-2-yl)-3-(substituted aryl)urea derivatives were designed and synthesized as our efforts to discover novel anti-Parkinsonian agents with improved pharmacological profile in haloperidol-induced catalepsy and oxidative stress in mice. All of the compounds were found to be active in alleviating haloperidol-induced catalepsy in mice. Furfuryl, 2- and/or 3-methoxy substituted phenyl derivatives emerged as potent agents. With exception of 2-chloro,5-trifluoromethyl-substituted analog, halogensubstituted derivatives exhibited moderate anti-Parkinsonian activity. Biochemical estimations of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) from brain homogenate were carried out to highlight the neuroprotective properties associated with them. Molecular docking studies of these compounds with adenosine A 2A receptor exhibited very good binding interactions and warrants further studies to confirm their binding with human A 2A receptor for the design and development of potent antagonists. Parameters for Lipinski's rule of 5 were calculated computationally because pharmacokinetic and metabolic behaviors in the body often are linked to the physical properties of a compound. None of the synthesized compounds violated Lipinski's rule, making them suitable drug candidate for the treatment of Parkinson's disease. © Springer Science+Business Media, LLC 2011.