Synthesis and biological evaluation of N-(benzene sulfonyl)acetamide derivatives as anti-inflammatory and analgesic agents with COX-2/5-LOX/TRPV1 multifunctional inhibitory activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 80; p. 129101
• Main Authors: Chen, Wenli, Xu, Qinlong, Ma, Xiaodong, Mo, Jiajia, Lin, Gaofeng, He, Guangwei, Chu, Zhaoxing, Li, Jiaming
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-01-2023
• Subjects: Acetamides - pharmacology; Acetamides - therapeutic use; Amides - therapeutic use; Analgesic; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Anti-inflammatory; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Benzene; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase 2 Inhibitors - therapeutic use; Edema - chemically induced; Edema - drug therapy; Molecular Docking Simulation; N-(benzene sulfonyl) acetamide derivatives; PK study; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; TRPV Cation Channels; MTDLs; FAAH; TX; PGER2; N-(benzene sulfonyl) acetamide derivatives; LTs; TRPV1; COX; PK study; Analgesic; β2-AR; LOX; NSAIDs; PK; Anti-inflammatory; PGs
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.129101

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•A series of novel N- (benzene sulfonyl) acetamide derivatives were designed and synthesized.•9a and 9b showed significant suppressive activity for COX-2, 5-LOX, and TRPV1.•9a displayed better bioavailability.•9a showed good anti-inflammatory analgesic activity in vivo.
In this study, a series of structurally novel N-(benzene sulfonyl) acetamide derivatives were designed, synthesized, and biologically evaluated as COX-2/5-LOX/TRPV1 multitarget inhibitors for anti-inflammatory and analgesic therapy. Among them, 9a and 9b displayed favorable COX-2 (9a IC50 = 0.011 μM, 9b IC50 = 0.023 μM), 5-LOX (9a IC50 = 0.046 μM, 9b IC50 = 0.31 μM) and TRPV1 (9a IC50 = 0.008 μM, 9b IC50 = 0.14 μM) inhibitory activities. The pharmacokinetic (PK) study of 9a in SD rats at the dosage of 10 mg/kg demonstrated a high oral exposure, an acceptable clearance and a favorable bioavailability (Cmax = 5807.18 ± 2657.83 ng/mL, CL = 3.24 ± 1.47 mL/min/kg, F = 96.8 %). Further in vivo efficacy studies illustrated that 9a was capable of ameliorating formalin-induced pain and inhibiting capsaicin-induced ear edema.