Comparative Antinociceptive Evaluation of Hofmeisterin I and Analogues from Hofmeisteria schaffneri in Zebrafish and Mice

Hofmeisteria schaffneri (Asteraceae)
is a medicinal plant used in Central Mexico for pain relief. Although
thymol- and northymol-derived metabolites contribute to its antinociceptive
activity, the low abundance of the latter has limited evaluation.
An optimized synthetic route to hofmeisterin I (1) improved
yields and reduced reaction times, enabling biological assessment.
Hofmeisterin I (1) and derivatives were tested in zebrafish
(Danio rerio) and murine formalin models.
Halogenated derivatives were toxic and minimally active, whereas the
acetylated analogue exhibited higher potency but limited safety. A
new nitrogen-containing imide analogue, namely, 1-(2-(5-bromo-2-hydroxy-4-methylphenyl)-2-oxoethyl)pyrrolidine-2,5-dione
(12), exhibited improved efficacy and a safer profile.
Mechanistic studies indicated the involvement of TRPV1, CB2, and PPARγ receptors, with modulation by the opioid and serotonergic
systems. Collectively, these findings highlight compound 12 as a promising antinociceptive scaffold. X-ray analyses of 1 and 12 are also reported.