In this contribution, four new compounds synthesized from 4-hydroxycoumarin and tyramine/octopamine/norepinephrine/3-methoxytyramine are characterized spectroscopically (IR and NMR), ...chromatographically (UHPLC-DAD), and structurally at the B3LYP/6-311++G*(d,p) level of theory. The crystal structure of the 4-hydroxycoumarin-octopamine derivative was solved and used as a starting geometry for structural optimization. Along with the previously obtained 4-hydroxycoumarin-dopamine derivative, the intramolecular interactions governing the stability of these compounds were quantified by NBO and QTAIM analyses. Condensed Fukui functions and the HOMO-LUMO gap were calculated and correlated with the number and position of OH groups in the structures. In vitro cytotoxicity experiments were performed to elucidate the possible antitumor activity of the tested substances. For this purpose, four cell lines were selected, namely human colon cancer (HCT-116), human adenocarcinoma (HeLa), human breast cancer (MDA-MB-231), and healthy human lung fibroblast (MRC-5) lines. A significant selectivity towards colorectal carcinoma cells was observed. Molecular docking and molecular dynamics studies with carbonic anhydrase, a prognostic factor in several cancers, complemented the experimental results. The calculated MD binding energies coincided well with the experimental activity, and indicated 4-hydroxycoumarin-dopamine and 4-hydroxycoumarin-3-methoxytyramine as the most active compounds. The ecotoxicology assessment proved that the obtained compounds have a low impact on the daphnia, fish, and green algae population.
The recently declared global pandemic of a new human coronavirus called SARS-CoV-2, which causes respiratory tract disease COVID-19, has reached worldwide resonance and global efforts are being made ...to look for possible cures. Sophisticated molecular docking software, as well as available protein sequence and structure information, offer the ability to test the inhibition of two important targets of SARS-CoV-2, furin (
FUR
) enzyme, and spike glycoprotein, or spike protein (
SP
), that are key to host cell adhesion and hijacking. The potential inhibitory effect and mechanism of action of acid-base forms of different antiviral drugs, dominant at physiological pH, chloroquine (
CQ
), hydroxychloroquine (
HCQ
), and cinanserin (
CIN
), which have been shown to be effective in the treatment of SARS-CoV-2 virus, is reported with the special emphasis on their relative abundances. On the other hand, the potential inhibitory effect of the dominant acid-base forms of quercetin (
Q
) and its oxidative metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2
H
) benzofuranone (
BZF
), which are constituents of traditional food products believed to exhibit antiviral effects, was also examined. The undertaken study includes the determination of the major energy contributions to the binding energy as well as in-depth analysis of amino acid residues at the active pocket and possible interactions. The approach that we propose here may be an additional strategy for combating the deadly virus by preventing the first step of the virus replication cycle. Preliminary research has shown that the investigated compounds exert an inhibitory effect against the SARS-CoV-2 furin enzyme and spiked glycoprotein through different acid-base forms. These investigations may be helpful in creating potential therapeutic agents in the fight against the SARS-CoV-2 virus. On the other hand, the results we predicted in this computational study may be the basis for new experimental
in vitro
and
in vivo
studies.
Identification of potential inhibitory effect of acid-base species of quercetin and its metabolite as well as chloroquine, hydroxychloroquine, and cinanserin, at physiological pH, on proteins essential for SARS-CoV-2 virus survival.
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•Conformational analysis of delphinidin, pelargonidin and malvin was performed.•OH and NO antiradical activity was examined theoretically and experimentally.•EPR measurements proved ...Dp, Pg and Mv was selective towards hydroxyl radical.•EPR measurements proved Dp, Pg and Mv was not selective towards nitric oxide.•Molecules investigated reacted with hydroxyl radical via HAT and SPLET mechanisms.
Naturally occurring flavonoids, delphinidin, pelargonidin and malvin, were investigated experimentally and theoretically for their ability to scavenge hydroxyl and nitric oxide radicals. Electron spin resonance (ESR) spectroscopy was used to determine antiradical activity of the selected compounds and M05-2X/6-311+G(d,p) level of theory for the calculation of reaction enthalpies related to three possible mechanisms of free radical scavenging activity, namely HAT, SET-PT and SPLET. The results obtained show that the molecules investigated reacted with hydroxyl radical via both HAT and SPLET in the solvents investigated. These results point to HAT as implausible for the reaction with nitric oxide radical in all the solvents investigated. SET-PT also proved to be thermodynamically unfavourable for all three molecules in the solvents considered.
Antioxidative properties of naturally occurring flavon-3-ol, fisetin, were examined by both cyclic voltammetry and quantum-chemical based calculations. The three voltametrically detectable ...consecutive steps, reflected the fisetin molecular structure, catecholic structural unit in the ring B, C3-OH, and C7-OH groups in the rings C and A. Oxidation potential values, used as quantitative parameter in determining its oxidation capability, indicated good antioxidative properties found with this molecule. Oxidation of the C3′C4′ dixydroxy moiety at the B ring occurred first at the lowest positive potentials. The first oxidation step induced fast intramolecular transformations in which the C3 hydroxy group disappeared and the product of this transformation participated in the second oxidation step. The highest potential of oxidation was attributed to the oxidation of C7 hydroxy group. The structural and electronic features of fisetin were investigated at the B3LYP/6-311++G** level of theory. Particularly, the interest was focused on the C3′ and C4′-OH sites in the B ring and on C3-OH site in the C ring. The calculated bond dissociation enthalpy values for all OH sites of fisetin clearly indicated the importance of the B ring and C3′ and C4′-OH group. The importance of keto−enol tautomerism has also been considered. The analysis also included the Mulliken spin density distribution for the radicals formed after H removal on each OH site. The results showed the higher values of the BDE on the C7-OH and C3-OH sites.
The global pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused many fatalities among people and significantly influenced the global economy. Since efficient treatment is ...not available, the computational methods in biology and chemistry are a promising starting point towards adequate medication. Three previously synthesized coumarin derivatives and their Pd(ii) complexes were examined for the binding affinity towards the M
protein of SARS-CoV-2 by molecular docking and compared to two Food and Drug Administration (FDA) drugs, cinanserin and chloroquine. All of the investigated compounds bind to the active position of the mentioned protein. Coumarin-Pd(ii) complexes showed higher binding affinities compared to the approved drugs. The bindings of the bis(3-(1-((3-chlorophenyl)amino)ethylidene)-chroman-2,4-dione) palladium(ii) complex, its corresponding ligand, and cinanserin to SARS-CoV-2 M
were further subjected to the molecular dynamics simulations. The binding free energies, computed by MM/PBSA approach were analyzed in detail and the importance of specific interactions outlined. These results showed that the molecules bearing structural similarity to the approved drugs and their complexes have the potential to inhibit the functional activity of SARS-CoV-2 protease and further experimental studies should be undertaken.
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•The hydrogen atom abstraction-radical addition mechanism was examined.•The radical adduct formation followed by hydrogen atom abstraction was proposed.•The decomposition of coumarins ...induced by HO• was analyzed by EPR and DFT approach.•Rate constants of mentioned reactions were obtained by the Transition State Theory.•Ecotoxicity study showed that products were less toxic than analyzed coumarins.
The excessive use of coumarins and their derivatives is becoming an ecological concern due to their toxicity towards different organisms. One of the possible ways of their removal is the advanced oxidation processes. The oxidative breakdown of 4-hydroxycoumarin and its two derivatives, induced by a very powerful oxidizer hydroxyl radical (HO•), was investigated experimentally and theoretically. The new mechanism, namely radical adduct formation followed by hydrogen atom abstraction (RAF-HAA), was proposed. The thermodynamic parameters and rate constants, calculated by the Transition State Theory for several active positions indicated a possible reaction in which less toxic products were obtained, as confirmed by the ecotoxicity assessment. The mechanism included the reaction with two HO• and the introduction of an additional OH group to the structure. These results were compared to the more common mechanism that includes HAA between the OH group of 4-hydroxycoumarin and HO•. Based on the Quantum Theory of Atoms in Molecules and Natural Bond Orbital theory the exo-coupled electron transfer (PCET) mechanism was pointed out as a dominant pathway. Radical addiction with another HO•, followed by keto-enol tautomerism, led to the formation of the stable final product, identical to one obtained in the RAF-HAA mechanism. The reaction rates for RAF-HAA were higher then those for pure HAA and reactions were more spontaneous, therefore leading to the conclusion that the newly proposed mechanism could be a dominant pathway for the aromatic molecules’ breakdown in the advanced oxidation processes.
Compounds from the plant world that possess antioxidant abilities are of special importance for the food and pharmaceutical industry. Coumarins are a large, widely distributed group of natural ...compounds, usually found in plants, often with good antioxidant capacity. The coumarin-hydroxybenzohydrazide derivatives were synthesized using a green, one-pot protocol. This procedure includes the use of an environmentally benign mixture (vinegar and ethanol) as a catalyst and solvent, as well as very easy isolation of the desired products. The obtained compounds were structurally characterized by IR and NMR spectroscopy. The purity of all compounds was determined by HPLC and by elemental microanalysis. In addition, these compounds were evaluated for their in vitro antioxidant activity. Mechanisms of antioxidative activity were theoretically investigated by the density functional theory approach and the calculated values of various thermodynamic parameters, such as bond dissociation enthalpy, proton affinity, frontier molecular orbitals, and ionization potential. In silico calculations indicated that hydrogen atom transfer and sequential proton loss-electron transfer reaction mechanisms are probable, in non-polar and polar solvents respectively. Additionally, it was found that the single-electron transfer followed by proton transfer was not an operative mechanism in either solvent. The conducted tests indicate the excellent antioxidant activity, as well as the low potential toxicity, of the investigated compounds, which makes them good candidates for potential use in food chemistry.
Free radicals often interact with vital proteins, violating their structure and inhibiting their activity. In previous studies, synthesis, characterisation, and the antioxidative properties of the ...five different coumarin derivatives have been investigated. In the tests of potential toxicity, all compounds exhibited low toxicity with significant antioxidative potential at the same time. In this paper, the radical scavenging activity of the abovementioned coumarin derivatives towards ten different radical species was investigated. It was found that all investigated compounds show good radical scavenging ability, with results that are in correlation with the results published in the previous study. Three additional mechanisms of radical scavenging activity were investigated. It was found that all three mechanisms are thermodynamically plausible and in competition. Interestingly, it was found that products of the Double Hydrogen Atom Transfer (DHAT) mechanism, a biradical species in triplet spin state, are in some cases more stable than singlet spin state analogues. This unexpected trend can be explained by spin delocalisation over the hydrazide bridge and phenolic part of the molecule with a low probability of spin pairing. Besides radical-scavenging activity, the pharmacokinetic and drug-likeness of the coumarin hybrids were investigated. It was found that they exhibit good membrane and skin permeability and potential interactions with P-450 enzymes. Furthermore, it was found that investigated compounds satisfy all criteria of the drug-likeness tests, suggesting they possess a good preference for being used as potential drugs.
The coumarin–orthoaminophenol derivative was prepared under mild conditions. Based on crystallographic structure, IR and Raman, 1H and 13C NMR spectra the most applicable theoretical method was ...determined to be B3LYP-D3BJ. The stability and reactivity parameters were calculated, in the framework of NBO, QTAIM and Fukui functions, form the optimized structure. This reactivity was then probed in biological systems. The antimicrobial activity towards four bacteria and three fungi species was examined and activity was proven. In vitro cytotoxic effects, against human epithelial colorectal carcinoma HCT-116 and human healthy lung MRC-5 cell lines, of the investigated substance are also tested. Compound showed significant cytotoxic effects on HCT-116 cells, while on MRC-5 cells showed no cytotoxic effects. The effect of hydroxy group in ortho-position on the overall reactivity of molecule was examined through molecular docking with Glutathione-S-transferases.
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•The cumarine derivative with o-aminophenol was synthesized under mild conditions.•The structure and spectroscopic properties of compound 3 are confirmed by DFT.•The MIC and IZ values of 3 are comparable to the commercially active drugs•Investigated substance revealed surprising effect on cancer cells HCT-116.•Possible interactions between 3 and Glutathione-S-transferase were revealed by MD.
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•The reactivity of coumarin derivatives towards HOO• was shown by ESR spectroscopy.•The thermodynamic and kinetic parameters for these process were calculated.•The radical adduct ...formation-hydrogen atom abstraction was the dominant mechanism.•The obtained AOPs products were less toxic towards aquatic animals.•The AOPs processes by HOO• are suggested for removal of stable aromatic compounds.
Coumarin derivatives are an example of stable molecules with very complex biodegradation routes in wastewaters. The use of advanced oxidation processes offers a way to their chemical modification to less toxic products. In this study, the experimental reactivity of 4-hydroxycoumarin (1) and its two derivatives towards hydroperoxyl radical (HOO•) was proven by the ESR spectroscopy. The absence of measurable concentration of carbon- and oxygen-centered radicals, except for DEPMPO-HOO• adduct, showed that stable products were formed in the reaction. Two novel mechanisms, namely hydrogen atom abstraction - radical–radical coupling (HAT-RRC) and radical adduct formation-hydrogen atom abstraction (RAF-HAA) were suggested as possible reaction routes between HOO• and coumarin derivatives. Thermodynamic and kinetic parameters were investigated in detail to explain the plausibility of these two mechanisms with special emphasis on the determination of the most active positions. The theoretical calculations were accompanied by the Natural Bond Orbital Theory and Quantum Theory of Atoms in Molecules. The thermodynamically preferred mechanism of the reaction was RAF-HAA, while the highest reaction rate was obtained for the position C3 of 1. The preferred mechanism was further verified by the UV–Vis spectrophotometry and excited state optimization. The examined routes lead to the formation of stable products with lower toxicity towards aquatic organisms, as shown by the eco-toxicology assessment.
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