Abstract
Xanthine oxidase (XO) is the enzyme responsible for the conversion of endogenous purines into uric acid. Therefore, this enzyme has been associated with pathological conditions caused by hyperuricemia, such as the disease commonly known as gout. Barbiturates and their congeners thiobarbiturates represent a class of heterocyclic drugs capable of influencing neurotransmission. However, in recent years a very large group of potential pharmaceutical and medicinal applications have been related to their structure. This great diversity of biological activities is directly linked to the enormous opportunities found for chemical change off the back of these findings. With this in mind, sixteen bis-thiobarbiturates were synthesized in moderate to excellent reactional yields, and their antioxidant, anti-proliferative, and XO inhibitory activity were evaluated. In general, all bis-thiobarbiturates present a good antioxidant performance and an excellent ability to inhibit XO at a concentration of 30 µM, eight of them are superior to those observed with the reference drug allopurinol (Allo), nevertheless they were not as effective as febuxostat. The most powerful bis-thiobarbiturate within this set showed in vitro IC50 of 1.79 μM, which was about ten-fold better than Allo inhibition, together with suitable low cytotoxicity. In silico molecular properties such as drug-likeness, pharmacokinetics, and toxicity of this promising barbiturate were also analyzed and herein discussed.
Highlights
Xanthine oxidase (XO) is a molybdoflavoprotein widely disseminated throughout the human body, and is present in the liver, intestine, lungs, kidneys, heart, brain, and plasma [1]
XO catalyzes the oxidative hydroxylation of hypoxanthine and xanthine into uric acid (UA) with the concomitant production of reactive oxygen species (ROS) [1]
Half-maximal inhibitory concentration (IC50 ) studies were performed for drugs used as a reference and for the most promising bis-thiobarbiturate in XO inhibitory, antioxidant, and cytotoxicity assays
Summary
Xanthine oxidase (XO) is a molybdoflavoprotein widely disseminated throughout the human body, and is present in the liver, intestine, lungs, kidneys, heart, brain, and plasma [1]. XO catalyzes the oxidative hydroxylation of hypoxanthine and xanthine into uric acid (UA) with the concomitant production of reactive oxygen species (ROS) [1] This enzyme is an important source of superoxide radicals and hydrogen peroxide, which contributes to oxidative stress and takes part in the aging process. Hyperuricemia is a predisposing factor of gout, whether by excessive production of UA or under-excretion by the kidneys and is considered a lifestyle-related syndrome. It has been associated with a high intake of foods rich in nucleic acids, such as red meats and seafood, leading to excessive production of UA [5,6]. Bis-thiobarbiturates have been scarcely explored except that they have been established as urease inhibitors [22] and were tested as antibacterials but without any relevant activity [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
