Characterization of thiobarbituric acid derivatives as inhibitors of hepatitis C virus NS5B polymerase

Lee, Jong-Ho; Lee, Sang-Yoon; Park, Mi Young; Myung, Heejoon

doi:10.1186/1743-422x-8-18

Cited by 21 publications

(5 citation statements)

References 26 publications

(21 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various barbituric acid derivatives have been studied as anti-inflammatory and anti-cancer compounds [37] – [39] . Thiobarbituric acid derivatives also have been studied as anti-tumor agents, uridine phosphorylase inhibitors, HIV-1 integrase inhibitors, and hepatitis C virus polymerase inhibitors [40] – [43] . An example of thiobarbituric acid derivative evaluated as a treatment for brain cancer is merbarone [5-(N-phenylcarboxamido)-2-thiobarbituric acid] which has a similar structure to CC-I.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

et al. 2014

View full text Add to dashboard Cite

The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu) nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O6-methylguanine methyltransferase (MGMT) but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Similarly thiobarbiturates behave as HIV integrase inhibitors [40], anticonvulsant and anesthetic [33], antibacterial [41,42], antifungal [43], antiviral [44] antitumor activities [45], tyrosinase inhibitors [46,47] and anticancer with anti-inflammatory activities [48].…”

mentioning

confidence: 99%

Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies

Rauf

Shahzad

Bajda

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

“…The treatment of infection caused by ureolytic bacteria with antimicrobials, however, often proved to be unsuccessful [ 13 ]. The barbiturates possessed a wide range of pharmacological applications, such as anticonvulsant, sedative, anxiolytic, urease inhibition [ 18 ], antifungal [ 19 ], antimicrobial [ 20 , 21 ], antitumor, antiviral [ 13 , 22 ] anti tuberculosis [ 23 ], mushroom tyrosinase inhibition [ 24 ], radio-sensitization [ 25 ], anti-inflammatory, anticancer [ 26 ], anesthetic [ 27 ], diaminopimelate aminotransferase inhibition [ 28 ], and anti-proliferative activities [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors

Barakat

Al‐Majid

Lotfy

et al. 2015

Chemistry Central Journal

View full text Add to dashboard Cite

BackgroundDiscovery of potent inhibitors of urease (jack bean) enzyme is the first step in the development of drugs against diseases caused by ureolytic enzyme.ResultsThirty-two derivatives of barbituric acid as zwitterionic adducts of diethyl ammonium salts were synthesized. All synthesized compounds (4a–z and 5a–s) were screened for their in vitro inhibition potential against urease enzyme (jack bean urease). The compounds 4i (IC50 = 17.6 ± 0.23 µM) and 5l (IC50 = 17.2 ± 0.44 µM) were found to be the most active members of the series, and showed several fold more urease inhibition activity than the standard compound thiourea (IC50 = 21.2 ± 1.3 µM). Whereas, compounds 4a–b, 4d–e, 4g–h, 4j–4r, 4x, 4z, 5b, 5e, 5k, 5n–5q having IC50 values in the range of 22.7 ± 0.20 µM–43.8 ± 0.33 µM, were also found as potent urease inhibitors. Furthermore, Molecular Dynamics simulation and molecular docking studies were carried out to analyze the binding mode of barbituric acid derivatives using MOE. During MD simulation enol form is found to be more stable over its keto form due to their coordination with catalytic Nickel ion of Urease. Additionally, structural–activity relationship using automated docking method was applied where the compounds with high biological activity are deeply buried within the binding pocket of urease. As multiple hydrophilic crucial interactions with Ala169, KCX219, Asp362 and Ala366 stabilize the compound within the binding site, thus contributing greater activity.ConclusionsThis research study is useful for the discovery of economically, efficient viable new drug against infectious diseases.Graphical abstract:STD. Thiourea (IC50 = 21.2 ± 1.3 µM)Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-015-0140-1) contains supplementary material, which is available to authorized users.

show abstract

Characterization of thiobarbituric acid derivatives as inhibitors of hepatitis C virus NS5B polymerase

Cited by 21 publications

References 26 publications

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies

Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors

Contact Info

Product

Resources

About