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Moving out of the CF3-land: synthesis, receptor affinity and in silico studies of NK1-receptor ligands containing pentafluorosulfanyl (SF5) group.

The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5-group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5-containing compounds. All the novel analogues exhibit detectable NK1R binding, with the best of them, compound 5a, binding only slightly worse (IC50 = 34.3 nM) than the approved NK1R-targeting drug, aprepitant (IC50 = 27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF5 group in our compounds occupies a position similar to that of one of CF3 groups of aprepitant as found in the crystal structure. Additionally, we checked on whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF5-group in the design of NK1R ligands.

Design of novel balanced COX 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 6m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6m 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-1β, as well as decreased production of prostaglandin E2 (PGE2), nitric oxide (NO), and reactive oxygen species (ROS). However, 6m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6m represents a promising candidate for further development as a new lead compound targeting inflammation.

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