Potent inhibitory activity of hydroxylated 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones on LPS-stimulated reactive oxygen species production in RAW 264.7 macrophages

• Published in: Bioorganic & medicinal chemistry letters Vol. 73; p. 128921
• Main Authors: Kunwar, Surendra, Min Lee, Su, Man Kadayat, Tara, Shrestha, Aarajana, Park, Pil-Hoon, Lee, Eung-Seok
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2022; Elsevier
• Subjects: 2-Benzylidene-3,4-dihydronaphthalen-1(2H)-ones; Anti-inflammatory agents; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; LPS-stimulated ROS inhibition; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-activity relationship study; 2-Benzylidene-3,4-dihydronaphthalen-1(2H)-ones; LPS-stimulated ROS inhibition; Anti-inflammatory agents; LPS; Structure-activity relationship study; ROS; CHALCONES; 2-Benzylidene-3, 4-dihydronaphthalen-1(2H)-ones; ROS PRODUCTION; DERIVATIVES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.128921

[Display omitted] •Sixty-six 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones were synthesized.•6 and 7‑Hydroxyl substituents exhibited potent ROS inhibitory activity.•Compound 28 displayed ROS inhibition fifty folds greater than reference compound.•meta–Halogen groups in Ring B are important for significant ROS inhibition. This study attempted to discover tetralone-derived potent ROS inhibitors by synthesizing sixty-six hydroxylated and halogenated 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones via Claisen-Schmidt condensation reaction. The majority of the synthesized and investigated compounds significantly inhibited ROS in LPS-stimulated RAW 264.7 macrophages. When compared to malvidin (IC50 = 9.00 µM), compound 28 (IC50 = 0.18 µM) possessing 6‑hydroxyl and 2‑trifluoromethylphenyl moiety showed the most potent ROS inhibition. In addition, the compounds 20, 31, 39, 45, 47–48, 52, 55–56, 58–60, and 62 also displayed ten folds greater ROS inhibitory activity relative to the reference compound. Based on the structure–activity relationship study, incorporating hydroxyl groups at the 6- and 7-positions of tetralone scaffold along with different halogen functionalities in phenyl ring B is crucial for potent ROS suppression. This study contributes to a better understanding of the effect of halogen and phenolic groups in ROS suppression, and further investigations on 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones will potentially lead to the discovery of effective anti-inflammatory agents.