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

摘要

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)-1 H -pyrazolo[3,4- d ]thiazolo[3,2- a ]pyrimidin-4-one ( 3b ) and 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1 H -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 K i ( 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)-1 H -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.