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Theoretical assessment of norfloxacin redox and photochemistry
Örebro University, School of Science and Technology.
Örebro University, School of Science and Technology.
2009 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, no 40, p. 10803-10810Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2009. Vol. 113, no 40, p. 10803-10810
National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-13209DOI: 10.1021/jp904671sISI: 000270362900026OAI: oai:DiVA.org:oru-13209DiVA: diva2:388327
Available from: 2011-01-17 Created: 2011-01-11 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Computational studies of photodynamic drugs, phototoxic reactions and drug design
Open this publication in new window or tab >>Computational studies of photodynamic drugs, phototoxic reactions and drug design
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The most important criterion when designing new drugs or improving old ones in order to prevent side effects or at least diminish them is drug safety. Treatment of all diseases generally needs use of either topical application or systemic medications (transported in the blood) during a certain period of time. These treatments are associated with a number of adverse effects. Photosensitivity is one of those side effects, with phototoxicity as one of the photosensitivity disorders. This adverse side effect arises because of a reaction between UV or visible-light and the drug molecule, its active form or photoproduct(s). Due to phototoxic side effect, unexpected symptoms varying from just a simple rash to severe cutaneous affectations can appear. Furthermore, biomolecular damage occurs once the drug-light interaction takes place persistently and ends with cell death.

Several drug families, such as over-the-counter drugs in the non-steroidal anti-inflammatory drug family of 2-arylpropionic acid derivatives, or prescription required fluoroquinolone drugs, have the capability to absorb mainly UV light radiation which in turn causes different phototoxic reactions by forming radical derivatives, reactive oxygen species or both. These may effect DNA, protein and lipid cell components leading to photogenotoxicity, photoallergy and lipid peroxidation, respectively. The photodegradation mechanisms of drugs belonging to the above mentioned families including ketoprofen, ibuprofen, flurbiprofen, naproxen, the active form of nabumetone, diclofenac and its main photoproduct, suprofen, tiaprofenic acid, naphazoline, norfloxacin and lomefloxacin are investigated in more detail in this thesis.

The results obtained by computational density functional theory (DFT) and time-dependent-DFT (TD-DFT) are in line with experimental data available to date. The studies provide detailed insight into the molecular basis and understanding of the full photodegradation mechanisms of drugs mentioned above. This also plays an important role in preventing or at least reducing the phototoxic adverse effects by enabling the development of safe drugs in this area. Hence, new modified non-steroid anti-inflammatory molecules were designed by computational techniques. Obtained results suggest possibility of their future usage as pharmaceuticals with reduced photodegradation and cyclooxygenase 1 induced adverse side effects compared to the parent compounds.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2009. p. 99
Series
Örebro Studies in Life Science ; 4
Keyword
NSAIDs, fluoroquinolone, photodegradation, phototoxicity, drug design, DFT, TD-DFT
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-8356 (URN)978-91-7668-694-2 (ISBN)
Public defence
2009-11-26, Hörsal M, Örebro universitet, Örebro, 13:15 (English)
Opponent
Supervisors
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2017-10-18Bibliographically approved

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Musa, Klefah A. K.Eriksson, Leif A.

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