Discovery of 3‑(Indol-5-yl)-indazole Derivatives as Novel Myeloid Differentiation Protein 2/Toll-like Receptor 4 Antagonists for Treatment of Acute Lung Injury

Acute
lung injury (ALI) is often caused by systemic inflammatory
responses. Targeting the myeloid differentiation protein 2/toll-like
receptor 4 (MD2–TLR4) complex may be a promising way to treat
Gram-negative bacterial-induced inflammatory disorders. In this study,
we report the design and synthesis of a new series of 3-(indol-5-yl)-indazoles,
which were evaluated for their anti-inflammatory activities in macrophages.
Among the analogues generated, the promising 3-(indol-5-yl)-indazole
analogue 22m inhibited lipopolysaccharide (LPS)-induced
expression of tumor necrosis factor alpha (TNF-α) and interleukin-6
(IL-6) in macrophages with IC50 values of 0.89 and 0.53
μM, respectively. Compound 22m was then identified
as an MD2–TLR4 antagonist in suppressing LPS-induced inflammatory
responses. In vivo administration of 22m significantly
inhibited macrophage infiltration and ameliorated histopathological
changes in lung tissues of LPS-challenged mice. Our studies have identified
a new 3-(indol-5-yl)-indazole, 22m, as a potent MD2–TLR4
inhibitor and lay the groundwork for future drug development of anti-inflammatory
agents for the treatment of ALI.