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

Abstract

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.

Keywords: Analgesic; Anti-inflammatory; N-(benzene sulfonyl) acetamide derivatives; PK study.