New nonsteroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity

• 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.

Ämnesord

NATURVETENSKAP  -- Kemi -- Fysikalisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Physical Chemistry (hsv//eng)

Nyckelord

NSAIDs

phototoxicity

docking

cyclooxygenase

interaction energy

selectivity

Biophysical chemistry

Biofysikalisk kemi

Kemi

Chemistry

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