Structural modification of natural axinelline A: Achieving reduced colitis side effects through balanced COX inhibition.

Marine natural products continue to hold great promise as potential candidates for the discovery of anti-inflammatory drug. In our previous investigation, we successfully synthesized axinelline A, a naturally occurring cyclooxygenase-2 (COX-2) inhibitor, as a promising anti-inflammatory lead compound. This study was to discover novel COX inhibitors with balanced inhibition, aiming to mitigate the severe adverse effects through further structural modification of axinelline A. Of the synthetic derivatives, compound 5e showed highest COX-2 inhibitory activity and balanced COX inhibition (IC50 = 1.74 µM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 16.32). The in vitro anti-inflammatory results indicated that 5e effectively suppressed the expression of pro-inflammatory mediators via the NF-κB signaling pathway rather than the MAPK signaling pathway. The in vivo ulcerative colitis assay demonstrated 5e significantly ameliorated the histological damages and showed strong protection against DSS-induced acute colitis. Therefore, our findings suggest that compound 5e exhibits potential as a promising anti-inflammatory agent with attenuated colitis-related adverse effects.

Insight from Linker Investigations: Discovery of a Novel Phenylbenzothiazole Necroptosis Inhibitor Targeting Receptor-Interacting Protein Kinase 1 (RIPK1) from a Phenoxybenzothiazole Compound with Dual RIPK1/3 Targeting Activity.

Necroptosis, a regulated cell death form, is a critical contributor in various inflammatory diseases. We previously identified a phenoxybenzothiazole SZM-610 as a RIPK1 and RIPK3 necroptosis inhibitor. We conducted extensive studies to investigate different chemical components' effects on antinecroptosis activity and RIPK1/3 activity. This study focused on replacing the linker in phenoxybenzothiazoles to assess its impact. Remarkably, compound 10, bearing a novel 3,2'-phenylbenzothiazole scaffold, exhibited fourfold more potent nanomolar activity than SZM-610. Unlike SZM-610, this compound inhibited RIPK1 (Kd = 17 nM) and eliminated RIPK3 inhibition at 5000 nM. Various linkages confirmed the 3,2'-phenylbenzothiazole superior potency. Moreover, this compound specifically inhibited necroptosis by inhibiting RIPK1, RIPK3, and MLKL phosphorylation. In a TNF-induced inflammatory model, it dose-dependently (1.25-5 mg/kg) protected mice from hypothermia and death, surpassing SZM-610's effectiveness. These findings highlight 3,2'-phenylbenzothiazole as a promising lead structure for developing drugs targeting necroptosis-related diseases.

Design of Balanced Cyclooxygenase Inhibitors Based on Natural Anti-inflammatory Ascidian Metabolites and Celecoxib.

The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6 m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6 m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, as well as decreased production of prostaglandin E2 (PGE2 ), nitric oxide (NO), and reactive oxygen species (ROS). However, 6 m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6 m represents a promising candidate for further development as a new lead compound targeting inflammation.

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

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, TNF-α, IL-6, and IL-1ß and reduced production of PGE2, 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.

Atom- and step-economic 1,3-thiosulfonylation of activated allenes with thiosulfonates to access vinyl sulfones/sulfides.

A new type of organocatalyzed 1,3-thiosulfonylation has been developed to straightforwardly access highly functionalized vinyl sulfones, which features mild conditions, atom- and step-economy, practicability, conciseness, and environmental friendliness. Moreover, these valuable products can be transformed to vinyl sulfides via a base-promoted isomerization. The versatile route can efficiently and rapidly introduce SCD3 groups with excellent levels of deuterium content (>99% D) by utilizing our newly developed SCD3 reagents. Gram-scale operations and further transformations are smoothly carried out, providing promising applications for drug discovery.

The Chapman rearrangement in a continuous-flow microreactor.

The Chapman rearrangement is of practical significance in pharmaceutical and fine chemical industries. It is a high temperature reaction with an exothermic nature in numerous cases. The conventional batch-wise synthesis is limited by its operational complexities, temperature control difficulties and scale-up hurdles. In this work, a microreactor-based continuous-flow approach was developed to perform the rearrangement in a highly controlled and safer manner. High conversions were obtained within short residence times (≤20 minutes). The detailed kinetics of this reaction, using 2,6-dichloro-phenyl N-phenyl benzimidate and 2-carbomethoxy-phenyl N-phenyl benzimidate as the representative reactants, was explored at varying temperatures to understand the intensified reaction behavior, and was modelled based on the obtained experimental data. The continuous process was scaled up to a 16-fold larger reactor volume by increasing the diameter of the microreactor while maintaining the residence time without further optimization. A very slight variation was observed in the conversion for the larger-sized flow system. Upscaling the batch reaction to a 10 times larger volume, by contrast, resulted in a dramatic decrease in the conversion. The simplicity of scaling up continuous-flow system was clearly demonstrated. A CFD model coupled with the obtained rearrangement kinetics was developed and well validated against the experimental data, which provided a robust platform for guiding the relevant process design and optimization of the continuous-flow processes. The results presented shed new light on the developments and applications of continuous-flow method for the classical Chapman rearrangement that require harsh high temperatures.