Synthesis and biological activity of pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one derivatives: in silico approach

Abstract

Xanthine oxidase (XO) is responsible for the pathological condition called gout. Inhibition of XO activity by various pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidine-4-one derivatives was assessed and compared with the standard inhibitor allopurinol. Out of 10 synthesized compounds, two compounds, viz. 3-amino-6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3b) and 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3g) were found to have promising XO inhibitory activity of the same order as allopurinol. Both compounds and allopurinol inhibited competitively with comparable Ki (3b: 3.56 µg, 3g: 2.337 µg, allopurinol: 1.816 µg) and IC₅₀ (3b: 4.228 µg, 3g: 3.1 µg, allopurinol: 2.9 µg) values. The enzyme–ligand interaction was studied by molecular docking using Autodock in BioMed Cache V. 6.1 software. The results revealed a significant dock score for 3b (−84.976 kcal/mol) and 3g (−90.921 kcal/mol) compared with allopurinol (−55.01 kcal/mol). The physiochemical properties and toxicity of the compounds were determined in silico using online computational tools. Overall, in vitro and in silico study revealed 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2–a]pyrimidin-4-one (3g) as a potential lead compound for the design and development of XO inhibitors.

Keywords::

• Pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidine-4-one
• inhibitory activity
• xanthine oxidase (XO)
• molecular modeling

Acknowledgements

The authors are thankful to the Director and Head, School of Life Sciences, SRTM University, Nanded for providing necessary facilities.

Declaration of interest

One of the author Ms. Ragini G. Bodade gratefully acknowledge the University Grants Commission (UGC)Delhi, India for financial assistance in the form of Rajiv Gandhi National Fellowship.