Newly Synthesized 3‑Indolyl Furanoid Inhibits Matrix Metalloproteinase‑9 Activity and Prevents Nonsteroidal Anti-inflammatory Drug-Induced Gastric Ulceration

Indomethacin,
a known nonsteroidal anti-inflammatory
drug (NSAID)
induces gastric inflammation, causing degradation of the extracellular
matrix by specific matrix metalloproteinases (MMPs). We investigated
the antiulcer efficacy of 3-indolyl furanoids (3g and 3c, i.e., methoxy substitution at 4- and 5-positions of the
indole ring, respectively), derived from indomethacin. Interestingly, 3g protected against indomethacin-induced gastropathy in vivo
by inhibiting MMP-9. Our work established a chemical modification
strategy for the development of safer NSAIDs. Moreover, in vitro and
in silico studies confirmed that 3g inhibited MMP-9 activity
with an IC50 value of 50 μM by binding to the catalytic
cleft of MMP-9, leading to ulcer prevention. Pharmacokinetics was
presented as the mean concentration–time profile in the rat
plasma, and the extraction efficiency was greater than 70%, showing
a Cmax of 104.48 μg/mL after 6.0
h (tmax) treatment with half-life and
area under the curve being 7.0 h and 1273.8 h μg/mL, respectively,
indicating the higher antiulcer potency of 3g.