title: Structure-based design, synthesis and molecular modeling studies of thiazolyl urea derivatives as novel anti-parkinsonian agents.
abstract: Synthesis of 1-(substituted aryl)-3-(thiazol-2-yl)urea derivatives was undertaken as our efforts to discover novel antiparkinsonian agents with improved pharmacological profile in haloperidol-induced catalepsy and oxidative stress in mice. Furfuryl, 2- and/or 3-methoxy substituted phenyl derivatives emerged as potent agents. With exception of 2-chloro,5-trifluoromethyl substituted analog, halogen substituted derivatives exhibited moderate antiparkinsonian activity. The results of biochemical investigations from brain homogenate of mice outline the importance of neuroprotective/antioxidant therapy for Parkinson's disease (PD), supporting the notion that the oxidative stress may play a significant role in the pathophysiological mechanisms underlying PD. 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 PD.
authors: NIMS Institute of Pharmacy, NIMS University, Jaipur-303121, Rajasthan, India. faizulazam@gmail.com
authors: Faizul
authors: F
authors: Azam
authors: Medapati Vijaya Vara
authors: MV
authors: Prasad
authors: Neelaveni
authors: N
authors: Thangavel
authors: Anil Kumar
authors: AK
authors: Shrivastava
authors: Govind
authors: G
authors: Mohan
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006220:Haloperidol / Q000009:adverse effects; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D011487:Protein Conformation; D043683:Receptors, Adenosine A2 / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry*; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000978:Antiparkinson Agents; D043683:Receptors, Adenosine A2; D013844:Thiazoles; D014508:Urea; D006220:Haloperidol