title: 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 microg, 3g: 2.337 microg, allopurinol: 1.816 microg) and IC(50) (3b: 4.228 microg, 3g: 3.1 microg, allopurinol: 2.9 microg) 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.
authors.affiliation: Biochemistry Research Laboratory, School of Life Sciences, Swami Ramanand Teerth Marathwada University, Nanded, India. cnkhobragade@rediffmail.com
authors.forename: Chandrahas N
authors.initials: CN
authors.lastname: Khobragade
authors.forename: Ragini G
authors.initials: RG
authors.lastname: Bodade
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Dawane
authors.forename: Shankaraiah G
authors.initials: SG
authors.lastname: Konda
authors.forename: Namdev T
authors.initials: NT
authors.lastname: Khandare
mesh_terms: D019295:Computational Biology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D005103:Expert Systems; D006074:Gout Suppressants / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013055:Spectrophotometry, Infrared; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: C554613:3-amino-6-(2-hydroxyphenyl)-1H-pyrazolo(3,4-d)thiazolo(3,2-a)pyrimidin-4-one; C554614:3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo(3,4-d)thiazolo(3,2-a)pyrimidin-4-one; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D011744:Pyrimidinones; D013844:Thiazoles; D014230:Triazoles; D014969:Xanthine Oxidase