Discovery of Novel Indazole Derivatives with Antineuroinflammatory Activity

Abstract

This study focuses on the critical role of microglia-mediated neuroinflammation in various neurological disorders. Utilizing the indazole heterocycle-a scaffold known for its structural plasticity and multi-target potential-as the core structure, a series of derivatives were designed and synthesized with the aim of screening and elucidating their anti-inflammatory activity and underlying mechanisms. The activities of the compounds were systematically evaluated in an in vitro LPS-stimulated BV-2 microglial model using Griess assay, MTT assay, qPCR, and western blotting. Among the 15 derivatives obtained, compound 5o exhibited the most potent anti-inflammatory activity (IC50 = 8.45 ± 0.64 μM). Its mechanism of action involves the regulation of microglial polarization-significantly suppressing M1 phenotype markers such as NO, IL-1β, IL-6, TNF-α, iNOS, and COX-2. Further mechanistic studies revealed that this effect is mediated through positive regulation nuclear translocation of Nrf2. In summary, this study demonstrates that the indazole derivative 5o exerts anti-neuroinflammatory and neuroprotective effects by inhibiting microglial M1 polarization, providing a promising lead compound and a robust pharmacological basis for the development of novel therapeutic strategies targeting neuroinflammatory diseases.