Synthesis of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists
The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were further characterized in the A(2A) binding assay and an A(1) selectivity assay. Selected examples exhibited excellent affinity for A(2A) and good selectivity versus the A(1) receptor.
[Show abstract] [Hide abstract] 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, halogen-substituted 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.0Comments 10Citations
- "These antagonists afford neuroprotective and antidyskinetic benefits (Schwarzschild et al., 2006) as well as increase the therapeutic index ratio between the therapeutic and unwanted side effects of L-dopa and other D 2 receptor agonists (Bara-Jimenez et al., 2003; Hauser et al., 2003). In addition to these, a large number of compounds having thiazole skeleton are potent adenosine A 2A receptor antagonists (Azam et al., 2009d; Cole et al., 2009; Nakajima et al., 2010; Sams et al., 2010) which have been shown to produce an increase in locomotor activity, a decrease of neuroleptic-induced catalepsy, a decrease of MPTP-induced motor disability, and several indications of neuroprotection in response to brain injury (Schwarzschild et al., 2003; Jenner et al., 2009; Nakajima et al., 2010). The importance of urea functionality can also be evidenced by its presence in potent A 2A receptor antagonists as well as in many biologically active compounds including neuroprotectants (Di Fabio et al., 1999; Choi et al., 2007). "
- [Show abstract] [Hide abstract] ABSTRACT: A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.0Comments 19Citations
- [Show abstract] [Hide abstract] ABSTRACT: A new 2-[(2-substituted phenyl-5-methyl-1,3-thiazolidin-4-one)-5-(2'-methylamino-4-phenyl-1',3'-thiazolyl]-1,3,4-thiadiazoles, 5(a-n) were synthesized from 2-substituted-benzylideneamino-5-[2'-methyl-amino 4'-phenyl-1',3'-thiazolyl]-1,3,4-thiadiazole, 4(a-n) using 2-amino-4-phenyl-1,3-thiazole as a starting material. The synthesised compounds have been screened in vitro for their antimicrobial activity against Bacillus subtilis, Escherichia coli. Klebsiella pneumoniae and Streptococcus aureus bacteria and Aspergillus niger, Aspergillus flavus, Fusarium oxisporium and Trichoderma viride fungi respectively. Some of the compounds displayed pronounced biological activity.0Comments 3Citations