Synthesis and Anti-Inflammatory Activity of the Natural Cyclooxygenase-2 Inhibitor Axinelline A and Its Analogues

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used medications to treat conditions such as arthritis, pain, and fever. They reduce inflammation by inhibiting cyclooxygenase (COX) enzymes that catalyze the committed step in prostaglandin (PG) biosynthesis. Despite their significant therapeutic benefits, many NSAIDS have undesirable adverse effects. The aim of this study was to discover novel COX inhibitors from natural sources. Here, we describe the synthesis and anti-inflammatory activity of the COX-2 inhibitor axinelline A (A1), which was isolated from Streptomyces axinellae SCSIO02208, and its analogues. Compared to the synthetic analogues, the natural product A1 has stronger COX inhibitory activity. Although A1 is more active against COX-2 than COX-1, its selectivity index is low; therefore, it may be classified as a nonselective COX inhibitor. Its overall activity is comparable to the clinically used drug diclofenac. In silico studies showed that A1 binds to COX-2 in a similar manner to diclofenac. Inhibition of COX enzymes by A1 in LPS-stimulated murine RAW264.7 macrophages resulted in suppression of the NF-κB signaling pathway, leading to reduced expression of pro-inflammatory factors such as iNOS, COX-2, TNFα, IL-6, and IL-1β and reduced production of PGE 2 , NO, and ROS. The potent in vitro anti-inflammatory activity of A1, together with its lack of cytotoxicity, makes it an attractive candidate for a new anti-inflammatory lead.

Novel Pyrazole Derivatives Bearing Carbonitrile and Substituted Thiazole Moiety for Selective COX‐2 Inhibition

“…COX‐1 inhibition was absent, while the potential for COX‐2 inhibition (with a cut‐off value of ≤5 μM [28] ) varied. Compounds 19 d , 19 e , 19 l , and 19 m demonstrated specific COX‐2 inhibition, with selectivity indexes of 31.57, 30.6, 31.09, and 48.99, respectively (Table 2 and Table 3).…”

“…(32.14) appear to have a higher inhibition profile for COX-2 in the NIH/3T3 healthy cell line (Table 2). Accordingly, it can be concluded that 4-OH-phenyl (19 c), 4- COX-1 inhibition was absent, while the potential for COX-2 inhibition (with a cut-off value of � 5 μM [28] ) varied. 3).…”

Synthesis and anti‐inflammatory activity of novel firocoxib analogues with balanced COX inhibition

“…Encouraged by our previously published findings (Fang et al, 2023;Ju et al, 2019Ju et al, , 2023 and as part of ongoing research toward the discovery of novel COX-2 inhibitors with well-balanced inhibitory activity, we have designed a new series of firocoxib analogs utilizing a molecular hybridization strategy. Amide bonds serve as pharmacophores or linking groups, playing an increasingly prominent role in the design and development of pharmaceuticals.…”

Design, synthesis, and anti-inflammatory activity of indole-2-formamide benzimidazole[2,1-b]thiazole derivatives

“…Melting points were obtained using a WRS-1B melting apparatus and were uncorrected. 1 H NMR and 13 C NMR spectra were recorded in DMSO-d 6 solution with a Bruker Instrument at 400 or 100 MHz, and peak positions are given in parts per million (d) downeld from tetramethylsilane as the internal standard. J values are given in Hz.…”