Syntheses and evaluation of the antioxidant activity of acitretin analogs with amide bond(s) in the polyene spacer

Ester analogs of the antipsoriatic drug acitretin were synthesized by coupling either anilines with N-protected indole-3-carboxylic acid, followed by deprotection and coupling with O-monoprotected dicarboxylic acids or Wittig reaction of indole-3-carboxaldehyde, 3-acetyl-1-tosylpyrrole and 4-amino-9-fluorenone with Ph3PCHCO2tBu, followed by N-deprotection, where necessary, and finally coupling with cinnamoyl fluorides. Corresponding free acids were obtained through TFA-mediated carboxyl group deprotection. Although these analogs and acitretin showed very low reducing abilities, analogs 5, 6, 8 and 12 strongly inhibited LOX with IC50 values ranging from 35–65 μM. Acitretin and its analogs 5–7, 10, 11 and 15 inhibited lipid peroxidation more strongly than trolox whereas acitretin and analog 4 were in vivo more potent anti-inflammatory agents on rat paw oedema induced by Carrageenan than indomethacin.

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