Quantitative structure-activity relationship study of human A₃ adenosine receptor antagonists: Derivatives of 2-aryl-1,2,4-triazolo[4,3-α]quinoxaline

Abstract

A quantitative structure-activity relationship (QSAR) study was conducted on the antagonistic activities of derivatives of 2-aryl-1,2,4-triazolo[4,3-α]quinoxaline at the human A₃ adenosine receptor. As per the structural framework, the title analogues were subdivided into two congeneric series, namely the 1,4-dione and the 4-amino-1-one series. A majority of substituents occurred at the R- and a limited number at the X-positions in both of these series. In the case of the 1,4-dione series, the derived significant QSAR equation revealed that those substituents exhibiting a larger field effect at R renders the molecule to more efficiently bind at the receptor site. The study also extrapolated the requirement of electron-donor substituents at the X-position which, at present, is regarded as insensitive to any interaction due to limited substitution. However, the X-position may be explored in a further synthetic study. From the derived correlation equation for the 4-amino-1-one series, it appeared that a strong electron-withdrawing substituent at R will enhance the pK_i value of a compound while a strong electron-donor at this position will have a detrimental effect on it. Based on correlation equations, derived using different electronic parameters, it may be interpreted that the two series of compounds attain different orientation inside the recognition site of the receptor.

Keywords::

• 2-Aryl-1,2,4-triazlo[4,3-α]quinoxaline derivatives
• human A3 receptor antagonist
• QSAR analysis
• Physicochemical properties

Acknowledgements

The authors are grateful to their Institution for providing the necessary facilities to complete this work.