Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design, synthesis, radiolabeling and biodistribution study
[Display omitted] •Novel thiobarbiturate derivatives were synthesized as urease inhibitors.•Anti-urease and antibacterial activities were investigated.•Compound 4 was the most potent.•Biodistribution study of radiolabeled 99mTc-compound 4 revealed a remarked uptake into infection induced in mice.•Mo...
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Published in | Bioorganic & medicinal chemistry Vol. 28; no. 23; p. 115759 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
OXFORD
Elsevier Ltd
01.12.2020
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | [Display omitted]
•Novel thiobarbiturate derivatives were synthesized as urease inhibitors.•Anti-urease and antibacterial activities were investigated.•Compound 4 was the most potent.•Biodistribution study of radiolabeled 99mTc-compound 4 revealed a remarked uptake into infection induced in mice.•Molecular docking analysis was also performed.
Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21–16.95 μM) superior to that of thiourea reference standard (IC50 = 20.04 μM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2020.115759 |