figshare
Browse

Design, Synthesis and Biological Evaluation of Ferrocenyl Thiazole and Thiazolo[5,4‑d]thiazole Catechols as Inhibitors of 5‑hLOX and as Antibacterials against Staphylococcus aureus. Structural Relationship and Computational Studies

Posted on 2020-07-06 - 19:14
In the search for new human 5-lipoxygenase (5-hLOX) inhibitors that could be used for the treatment of a variety of inflammation-related diseases, three new ferrocenyl complexes derived from 2,4-thiazole and thiazolo­[5,4-d]­thiazole ((η5-C5H4-2,4-thiazol-3,4-dihydroxyphenyl)­Fe­(η5-C5H5) (3), (η5-C5H4-2,4-thiazol-phenyl)­Fe­(η5-C5H5) (4), and (η5-C5H4-thiazolo­[5,4-d]­thiazole-3,4-dihydroxybenzene)­Fe­(η5-C5H5) (5)) were synthesized and evaluated. A cooperative effect among the ferrocenyl, thiazole, and catechol fragments was evidenced and corroborated on evaluating the activity of the ferrocenyl (1) and catechol (2) precursors and additionally the organic derivative 6, similar to the NDGA structure. The thiazole derivative 3 was the best 5-hLOX inhibitor (85.8% inhibition, IC50 = 0.9 ± 0.7 μM for 5-hLOX and 22 ± 1.1 μM in human cells), followed by complex 4 (74.6% inhibition, IC50 = 5.4 ± 1.7 μM), which presents low cytotoxicity (>250 μM), associated with the absence of OH groups (decrease in reactive oxygen species generation). Molecular dynamic and docking studies of 3 and 4 showed that the ferrocenyl fragment is oriented to the active iron­(III) site present in 5-hLOX; kinetics and FRAP assays together with electrochemical analysis suggest a redox mechanism mediated by water (Fe­(III) from enzyme/Fe­(II) from complex) accompanied by the blocking of the substrate approach, being consistent with competitive inhibition. The ferrocenyl, together with the thiazole and catechol fragments, drastically improves the antibacterial activity (percentage of bacterial growth inhibition of 85.5% and a MIC value of 25 μg/mL for 3), and an ROS assay suggests another mechanism for the antibacterial activity for Staphylococcus aureus.

CITE THIS COLLECTION

DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
or
Select your citation style and then place your mouse over the citation text to select it.

SHARE

email
need help?