Synthesis and biological evaluation of novel azetidine derivatives as dopamine antagonist
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Med Chem Res DOI 10.1007/s00044-013-0579-3
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel azetidine derivatives as dopamine antagonist Shashikant D. Metkar • Manish S. Bhatia Uday V. Desai
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Received: 6 September 2012 / Accepted: 11 March 2013 Ó Springer Science+Business Media New York 2013
Abstract In this study, azetidine derivatives were evaluated for their potency as dopaminergic antagonist. The study comprised derivatives substituted in 3-position with amide moiety. Further, the phenyl moiety of amide was modified at 2, 3, or 4-position. The substituted compounds were biologically evaluated for their affinity for D2 and D4 receptors. The most potent D2 and D4 antagonist among these compounds appeared to be the N-(1-benzhydrylazetidin-3yl)-2-bromo-benzamide and N-(1-benzhydrylazetidin-3yl)-4-bromo-benzamide, respectively. Various docking interactions of CPPMA with the D4 receptor and the same for compound 5 i.e., N-(1-benzhydryl-azetidin3yl)-4-bromo-benzamide were found to have good correlation with observed biological activity. Keywords Epichlorohydrin Benzhydrylamines Azetidine D2, D4 antagonist
Introduction Azetidines are an important class of four-membered monocyclic aza-heterocyclic compounds with remarkable biological activities, which made them an interesting synthetic topic. Compared to their higher homologous counterparts, azetidine ring finds wide application as a pharmacological
tool in many drugs or bioactive compounds. (Pettersson et al., 2011; Rajasekaran et al., 2010) Despite their remarkable biological importance due to the difficulty in formation of four member ring and strained nature, azetidines have been relatively less explored class of compounds. In fact, compounds bearing azetidine moiety find wide application in reducing blood cholesterol levels (Kvarebo et al., 2005), as human chymase inhibitors (Aoyana et al., 2001), as gamma amino butyric acid reuptake inhibitors (Faust et al., 2010; Metzner et al., 2004), as antifungals (Singh et al., 2006), as antibacterials (O’Dowd et al., 2008), as well as antidepressants (Melloni et al., 1979). The literature survey revealed that sulpiride (Ratomponirina et al., 2003) and a few compounds belonging to FAUC series (Heindl et al., 2003; Abbas et al., 2009; Orr, 1986; Barth et al., 1997; Woodhead et al., 2006) have been widely used as dopamine antagonists. Typically these potentially bioactive compounds are characterized by the presence of amide/peptide bond and a two to three carbon bridge separating the amide nitrogen from nitrogen present in a heterocycle.
M. S. Bhatia (&) Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur 416013, India e-mail: [email protected]
O NH
N H2N
SO2 O Sulphiride
S. D. Metkar U. V. Desai Department of Chemistry, Shivaji University, Vidyanagari, Kolhapur 416004, India
Cl
O
N H
C3H7
O N FAUC-21
Taking into account these facts as well as the structures of azetidine motif, we planned to synthesize few derivatives of azetidine having bot
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