Year: 2026
Type: preprint
Abstract: The interleukin-6(IL-6) signaling pathway plays a critical role in mediating inflammatory responses implicated in various diseases, including rheumatoid arthritis. The synthesis of new class of 1,3-indanedione AKS1-AKS12 was guided by their favorable binding affinities to the IL-6 receptor identified through in-silico approaches in wild and mutated-proteins. Characterization of synthesized compounds was performed using FTIR, NMR, and Mass spectroscopy. In-vitro assays, including MTT, RT-PCR, and ELISA, were conducted to assess the efficacy of AKS1-AKS12 in modulating IL-6 overexpression. Acute oral toxicity studies were conducted to evaluate the safety profiles of the compounds, while a rat model of Complete Freund’s adjuvant (CFA) arthritis was employed to assess their therapeutic efficacy. Among the synthesized compounds, AKS7 and AKS11 demonstrated potent inhibition of IL-6 overexpression, supported by in-vitro experimental validation. Furthermore, acute oral toxicity studies revealed favorable safety profiles of the compounds, and in-vivo studies in a rat model of CFA arthritis demonstrated significant mitigation of arthritis symptoms. Downregulation of key inflammatory genes IL-6 and STAT-3 further supported the candidacy of AKS7 and AKS11 as IL-6 inhibitors. Our synthesized compounds, particularly AKS7 and AKS11, exhibit dual modulatory actions on the IL-6 signaling pathway, effectively inhibiting IL-6-mediated inflammation at both the protein and mRNA levels. Additionally, the compounds also downregulated the STAT-3 gene which is overexpressed during the IL6 activation in IL-6/STAT-3 pathway. These findings underscore the therapeutic potential of our designed compounds for conditions associated with dysregulated IL-6/STAT-3 signaling pathways, AKS7 and AKS11 as promising candidates for the treatment of IL-6-mediated inflammatory disorders.
Source: Research Square
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204759997