| 1. |
- Musa, Klefah A K, et al.
(author)
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Mechanism of Photoinduced Decomposition of Ketoprofen
- 2007
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In: Journal of Medicinal Chemistry. - Washington, DC : American Chemical Society. - 0022-2623 .- 1520-4804. ; 50:8, s. 1735-1743
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Journal article (peer-reviewed)abstract
- UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen.
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| 2. |
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| 3. |
- Musa, Klefah A. K., et al.
(author)
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New nonsteroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity
- 2011
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In: International Journal of Quantum Chemistry. - : Wiley-Blackwell. - 0020-7608 .- 1097-461X. ; 111:6, s. 1184-1195
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Journal article (peer-reviewed)abstract
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretic, analgesic, and anti-inflammatory agents. However, they are also associated with a range of side effects, from phototoxicity due to excited state induced decarboxylation to severe conditions in the gastrointestinal tract caused by inhibition of the COX-1 isoform of the target cyclooxygenase enzyme. In the current work, new derivatives of the three NSAIDs ketoprofen, ibuprofen, and naproxen were designed. Their photochemistry was explored using hybrid-density functional theory (B3LYP/6-31G(d,p)) and time-dependent (TD) DFT, showing that the compounds will have significantly reduced propensity to decarboxylate from the first excited triplet state. In addition, docking studies were carried out for these new molecules to explore their activity and selectivity toward the two isoforms of the COX enzyme. The results show that most compounds have increased activity toward the COX enzymes, and in general are more selective toward the COX-2 target isoform. The results from this study suggest that the new modified molecules could be used in the future as NSAIDs with considerably reduced side effects.
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| 4. |
- Musa, Klefah A.K., et al.
(author)
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Photochemical and photophysical properties, and photodegradation mechanism, of the non-steroid anti-inflammatory drug Flurbiprofen
- 2009
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In: Journal of Photochemistry and Photobiology A. - Amsterdam : Elsevier. - 1010-6030 .- 1873-2666. ; 202:1, s. 48-56
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Journal article (peer-reviewed)abstract
- The photodegradation mechanism of the widely used non-steroidal anti-inflammatory drug 2-(4-phenyl-3-fluorophenyl) propanoic acid, Flurbiprofen, and its photochemical and photophysical properties have been investigated by means of computational quantum chemistry at the DFT-B3LYP/6-31G(d,p) level. Comparison of computed and experimental singlet and triplet–triplet absorption spectra point to that most experiments, using a range of different solvents, are conducted on the neutral, protonated form of Flurbiprofen. The deprotonated acid, which should dominate at physiological pH, shows no sign of decarboxylation from the lowest singlet excited states, whereas from its first excited triplet state this should readily occur by passing over an energy barrier of <0.5 kcal/mol. Further reactions in the proposed photodegradation mechanism, after decarboxylation, as well as the probability for reactive oxygen species formation are discussed in detail. The generation of the corresponding peroxyl radical from the decarboxylated radical and molecular oxygen is strictly exergonic and occurs without barrier under aerobic conditions. The thus formed peroxyl radical will in turn be capable of initiating propagating lipid peroxidation processes.
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| 5. |
- Musa, Klefah A. K., et al.
(author)
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Photodegradation Mechanism of Nonsteroidal Anti-Inflammatory Drugs Containing Thiophene Moieties : Suprofen and Tiaprofenic Acid
- 2009
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In: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 113:32, s. 11306-11313
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Journal article (peer-reviewed)abstract
- The photodegradation of nonsteroid anti-inflammatory drugs suprofen, 2-[4-(2-thienoyl)phenyl]propionic acid, and tiaprofenic acid, 2-(5-benzoyl-2-thienyl)propanoic acid, is studied by means of density functional theory. Besides the redox properties of the neutral species, we report on absorption spectra and degradation pathways involving excitation, intersystem crossing to the T-1 state. and spontaneous decarboxylation of the deprotonated species of each drug. The energetics and properties of the suprofen and tiaprofenic acid systems are found to be very similar to those of the highly photolabile benzyl analogue ketoprofen. Mechanisms leading to the formation of a closed-shell decarboxylated ethyl species, as well as peroxyl radicals capable of initiating lipid peroxidation reactions, are discussed.
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| 6. |
- Musa, Klefah A. K., et al.
(author)
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Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct
- 2009
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In: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 11:22, s. 4601-4610
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Journal article (peer-reviewed)abstract
- Diclofenac (DF) is a widely used non-steroid anti-inflammatory drug, associated with a range of side effects. The phototoxicity of DF is studied herein employing computational quantum chemistry at the B3LYP/6-31G(d,p) level of theory. The results show that the drug readily absorbs radiation from the UV-region. The deprotonated form spontaneously dechlorinates from its triplet state leading to ring closure and formation of an active photoproduct: chlorocarbazole acetic acid, CCA. The formed CCA is also photodegraded easily from its deprotonated triplet state. Photodegradation routes of deprotonated CCA are decarboxylation (barrier less than 4.5 kcal mol(-1)) and dechlorination (barrier around 6.2 kcal mol(-1)). The energy barrier required for dechlorination to take place from the neutral from is about 20 kcal mol(-1). The differences between the molecular orbitals of the neutral and the deprotonated forms of DF and CCA and spectra obtained using time-dependent density-functional theory (TD-DFT), in addition to the different radical and oxygenated intermediate species formed during the photodegradation mechanism, are discussed in more detail. The theoretical results obtained herein are in line with the experimental results available to date.
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| 7. |
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| 8. |
- Musa, Klefah A. K., et al.
(author)
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Theoretical assessment of naphazoline redoxchemistry and photochemistry
- 2007
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In: Journal of Physical Chemistry B. - Washington, DC : American Chemical Society. - 1520-6106 .- 1520-5207. ; 111:15, s. 3977-3981
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Journal article (peer-reviewed)abstract
- The imidazoline derivative naphazoline (2-(1-naphtylmethyl)-2-imidazoline) is an α2-adrenergic agonist used as non-prescription eye and nasal preparations. Besides its functionality in generating vascoconstriction and decongestion in the patient, the toxicity, ROS generating capability, and recently also possible antioxidant capacity of the compound have been reported in the literature. In the current work the structural and electronic features of the drug are explored, using computational chemical tools. Electron affinities, ionization potentials, and excitation energies are reported, as well as charge and spin distributions of various forms of the drug. The difference in photochemical behavior between the protonated and unprotonated (basic) species is explained by the molecular orbital distributions, allowing for efficient excitation quenching in the basic structure but clear naphthalene to imidazolene charge transfer upon HOMO→ LUMO excitation in the protonated form, enabling larger intersystem crossing capability to the imidazole localized excited triplet and a resulting higher singlet oxygen quantum yield.
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| 9. |
- Musa, Klefah A. K., et al.
(author)
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Theoretical assessment of norfloxacin redox and photochemistry
- 2009
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In: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 113:40, s. 10803-10810
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Journal article (peer-reviewed)abstract
- Norfloxacin, 1-ethyl-6-fluoro-1,4-dihydo-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyli c acid, NOR, is an antibiotic drug from the fluoroquinoline family. The different protonation states of this drug formed throughout the pH range is studied by means of density functional theory (DFT) and the spectra of the NOR species computed using time-dependent DFT. Details about their photochemistry are obtained from investigating the highest occupied and lowest unoccupied molecular orbitals. The predominant species under physiological pH, the zwitterion, is the most photoliable one, capable of producing singlet oxygen or/and superoxide radical anions from its triplet state. In addition, the main photodegradation step, defluorination, occurs more easily from this species compared with the other forms. The defluorination from the excited triplet state requires passing a barrier of 16.3 kcal/mol in the case of the zwitterion. The neutral and cationic forms display higher transition barriers, whereas the reaction path of defluorination is completely endothermic for the anionic species. The theoretical results obtained herein are in line with previous experimental data.
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| 10. |
- Musa, Klefah A. K., et al.
(author)
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Theoretical Study of Ibuprofen Phototoxicity
- 2007
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In: Journal of Physical Chemistry B. - Washington, DC : American Chemical Society. - 1520-6106 .- 1520-5207. ; 111:46, s. 13345-13352
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Journal article (peer-reviewed)abstract
- The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C−C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.
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