posted on 2022-12-09, 18:33authored byMarianna Potenza, Assunta Giordano, Maria G. Chini, Anella Saviano, Christian Kretzer, Federica Raucci, Marina Russo, Gianluigi Lauro, Stefania Terracciano, Ines Bruno, Maria Iorizzi, Robert K. Hofstetter, Simona Pace, Francesco Maione, Oliver Werz, Giuseppe Bifulco
The application of
a multi-step scientific workflow revealed
an
unprecedented class of PGE2/leukotriene biosynthesis inhibitors
with in vivo activity. Specifically, starting from
a combinatorial virtual library of ∼4.2 × 105 molecules, a small set of compounds was identified for the synthesis.
Among these, four novel 2-aminoacyl-1,3,4-thiadiazole derivatives
(3, 6, 7, and 9) displayed marked anti-inflammatory properties in vitro by strongly inhibiting PGE2 biosynthesis, with IC50 values in the nanomolar range. The hit compounds also efficiently
interfered with leukotriene biosynthesis in cell-based systems and
modulated IL-6 and PGE2 biosynthesis in a lipopolysaccharide-stimulated
J774A.1 macrophage cell line. The most promising compound 3 showed prominent in vivo anti-inflammatory activity
in a mouse model, with efficacy comparable to that of dexamethasone,
attenuating zymosan-induced leukocyte migration in mouse peritoneum
with considerable modulation of the levels of typical pro-/anti-inflammatory
cytokines.