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.
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Flores, Erick; Muñoz-Osses, Michelle; Torrent, Claudia; Vásquez-Martínez, Yesseny; Gómez, Alejandra; Cortez-San Martin, Marcelo; et al. (2020). 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. ACS Publications. Collection. https://doi.org/10.1021/acs.organomet.0c00284