Improved synthesis, molecular modeling and anti-inflammatory activity of new fluorinated dihydrofurano-naphthoquinone compounds

• Published in: Bioorganic & medicinal chemistry letters 2024-05, Vol.104, p.129714-129714, Article 129714
• Main Authors: Nguyen, Ha Thanh, Pham-The, Hai, Tuan, Anh Nguyen, Thu, Ha Nguyen Thi, Thi, Tuyet Anh Dang, Le-Nhat-Thuy, Giang, Thi, Phuong Hoang, Thi, Quynh Giang Nguyen, Van Nguyen, Tuyen
• Format: Article
• Language: English
• Subjects: Anti-inflammation; Fluorinated dihydrofurano-napthoquinones; inhibitor of NO production and pro-inflammatory cytokines; Molecular docking simulation; Multi-component reaction
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129714

[Display omitted] •New fluorinated dihydrofurano-napthoquinone compounds were synthesized.•Their nitric oxide (NO) inhibitory activities were evaluated.•Their pro-inflammatory cytokine (IL-1β and IL-6) inhibitory activities were evaluated.•Product 8b, 8d, 8e, 8k exhibited good NO, IL-1β and IL-6 inhibitory activities.•The interaction of 8b, 8d, and 8e with some pro-inflammatory mediators was predicted.•Physicochemical and pharmacokinetic computations were also conducted. A series of new fluorinated dihydrofurano-napthoquinone compounds were sucessfully synthesized in good yields using microwave-assisted multi-component reactions of 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, and pyridinium bromide. The products were fully characterized using spectroscopic techniques and evaluated for their anti-inflammatory activity using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Among 12 new compounds, compounds 8b, 8d, and 8e showed high potent NO inhibitory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 values ranging from 1.54 to 3.92 µM. The levels of pro-inflammatory cytokines IL-1β and IL-6 in LPS-stimulated RAW264.7 macrophages were remarkably decreased after the application of 8b, 8d, 8e and 8k. Molecular docking simulations revealed structure–activity relationships of 8b, 8d, and 8e toward NO synthase, cyclooxygenase (COX-2 over COX-1), and prostaglandin E synthase-1 (mPGES-1). Further physicochemical and pharmacokinetic computations also demonstrated the drug-like characteristics of synthesized compounds. These findings demonstrated the importance of fluorinated dihydrofurano-napthoquinone moieties in the development of potential anti-inflammatory agents.