Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

Abstract

A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a–4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 μM). In the DCF-DA assay, the 4′-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3′-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC50 11.4, 4.1, and 8.7 μM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. in silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 μΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60–97%) values.

Synthesis, Conformational Analysis and ctDNA Binding Studies of Flavonoid Analogues Possessing the 3,5-di-tert-butyl-4-hydroxyphenyl Moiety

“…However, in alkaline conditions, 3,5-di- tert -butyl-4-hydroxybenzaldehyde ( 2 ) is in equilibrium with the corresponding quinone methide anion, which predominates and significantly lowers the electrophilic character of the benzaldehyde [ 39 , 46 ]. As is very nicely explained in the work of Adams [ 40 ], in acidic conditions, the protonation of the aldehyde group enhances its electrophilic character and the benzenoid tautomers are more stable than the quinoid tautomer, which is unreactive. Thus, we decided to perform the reaction in acidic conditions and used dry methanol saturated with hydrogen chloride ( Scheme 1 ).…”

“…The ability of the synthesized compounds to inhibit AAPH induced linoleic acid oxidation was evaluated following the method described in the reference [ 40 ]. The results are presented in Table 1 .…”

Synthesis, photophysical properties, anticancer evaluation, and molecular docking studies of new pyrimidine linked 4‐arylidene‐thiazolidin‐4‐ones as potent anticancer agents

“…Analogues based on pyrimidine and its annulated heterocyclic compounds have garnered significant interest due to their diverse biological properties, including antimicrobial [1][2][3], anti-inflammatory [4,5], antioxidant [6,7], antiviral [8], and antitumour [9][10][11][12] effectiveness.…”

“…Analogues based on pyrimidine and its annulated heterocyclic compounds have garnered significant interest due to their diverse biological properties, including antimicrobial [1–3], anti‐inflammatory [4, 5], antioxidant [6, 7], antiviral [8], and antitumour [9–12] effectiveness. Pyrimidines were prominent early in the history of organic chemistry as ‘ m ‐diazines’ arising from uric acid catabolism [13].…”

New Azido Coumarins as Potential Agents for Fluorescent Labeling and Their “Click” Chemistry Reactions for the Conjugation with closo-Dodecaborate Anion

“…Coumarins are an important class of natural products that exhibits various types of biological activity, such as anti-inflammatory [ 1 , 2 , 3 ], anticonvulsant [ 4 ], antibacterial [ 5 , 6 , 7 ], antiviral [ 8 , 9 , 10 ], anticancer [ 11 , 12 , 13 , 14 , 15 ] and others [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Along with biological activity, coumarins have been known to possess unique fluorescent properties, especially when substituted with an electron donating group at the C-7 and an electron withdrawing group at the C-3 position of coumarin moiety.…”