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

Abstract

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.

Exploring the mechanism of astaxanthin against lipopolysaccharide-induced acute lung injury by network pharmacology and experimental validation

“…Studies have shown that LPS promotes the excessive production of in ammatory mediators by activating the TLR4/Myd88 signaling pathway, leading to lung damage and ALI progression [27,28]. Recent studies have shown that several natural products modulate the in ammatory response by inhibiting the TLR4/NF-κB signaling pathway [29][30][31][32][33]. Our results showed that astaxanthin inhibit the TLR4/MyD88/NF-κB signaling pathway.…”

An Indole-2-Carboxamide Derivative, LG4, Alleviates Diabetic Kidney Disease Through Inhibiting MAPK-Mediated Inflammatory Responses

“…[31][32][33] LG4, a novel indole compound developed in our laboratory, has been shown to exert anti-inflammatory effects both in vitro and in vivo. 34 In this study, we found that LG4 treatment remarkably reversed the function, histological abnormalities, fibrosis, and inflammation in the kidneys of T1DM mice without affecting their blood glucose and body weight. The effect of LG4 is highly related to its antiinflammation property.…”

Current and Future Roles of Artificial Intelligence in Medicinal Chemistry Synthesis

“…How the availability of starting materials affects the SA can be seen by enumerating methylated variants of compound A ( 57 ) followed by an evaluation using ASKCOS’s retrosynthesis tree search. While an expert chemist can easily infer that compound A is disconnected by amide formation and C–C cross-coupling, the general knowledge of the commercial availability of the methylated starting materials is less likely.…”