tnf-a-in-6

TNF-α-IN-6 is an orally efficacious, allosteric inhibitor of TNFα (K_D = 6.8 nM).

3-Hydroxykynurenamine, also known as 3-Hydroxy-L-kynurenamine or 3-HKA, is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction.This compound is unstable in powder form and other related salt forms are recommended.

1. Linalool (Linalol), a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. 2. Linalool was protected against LPS/GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-κB inhibition. 3. Linalool biosynthesis and accumulation might be involved in plant defense against bacterial and fungal pathogens and be associated with field resistance to citrus canker. 4. Linalool significantly increased the expression of antioxidant enzymes regulated by Nrf-2 and diminished lung tissue levels of several pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL)-6.

ABzOH is a benzoic acid derivative, similar in structure to non-steroidal anti-inflammatory drugs such as aspirin, with anti-inflammatory, anti-tumor and anti-proliferative effects. ABzOH can not only inhibit the expression of tumor necrosis factor-α (TNF-a), interleukin-1β (IL-1β), interleukin-6 (IL-6) and other pro-inflammatory cytokines, but also inhibit breast cancer, lung cancer and pancreatic cancer.

PDE4B-IN-6 (Compound 4i) is a potent and highly selective inhibitor of phosphodiesterase 4B (PDE4B) with an IC50 of 7.42 nM. As a roflumilast analogue, it exhibits significantly higher selectivity for PDE4B over PDE4A (IC50 = 1540 nM, ~195-fold) and PDE4C (IC50 = 1260 nM, ~169-fold). PDE4B-IN-6 exerts anti-inflammatory effects by elevating intracellular cAMP levels and suppressing the expression of the pro-inflammatory cytokine TNF-α. Additionally, it demonstrates good antioxidant properties and low cytotoxicity, making it suitable for research on chronic obstructive pulmonary disease (COPD) and related inflammatory conditions.

4-Deoxypyridoxine (4-DPD) is a vitamin B6 antimetabolite with diverse biological activities. It inhibits transport of pyridoxine , pyridoxal, and pyridoxamine in and reduces growth of S. carlsbergensis cells. 4-DPD inhibits sphingosine-1-phosphate (S1P) lyase and reduces cyclic stretch-induced apoptosis in alveolar epithelial MLE-12 cells. 4-DPD (5 mg, i.p.) reduces lysyl oxidase activity by 26% and reduces collagen and elastin crosslinking, resulting in limb abnormalities in chick embryos. It decreases latency to first seizure in mice (ED50 = 1 mmol/kg) and increases the occurrence and duration of myoclonic responses in baboons with photosensitive epilepsy. 4-DPD reduces TNF-α and IL-6 production in mice infected with T. spiralis.

Beclomethasone 17-propionate is a glucocorticoid that is the active metabolite of Beclomethasone dipropionate (BDP). As a glucocorticoid receptor (GR) agonist, 17-BMP has a 13-fold higher affinity than BDP and inhibits the production of pro-inflammatory cytokines, such as CXCL8, TNF-α, and IL-6, thus exerting an anti-inflammatory effect, and it is mainly used in the treatment of asthma and allergic rhinitis.

Luteolin-7-rutinoside is a natural product that alleviates LPS-induced acute liver injury by inhibiting the PI3K/AKT/AMPK/NF-κB signaling pathways and suppressing TNF-α, IL-6, and IL-1β.

CU-T12-9 is a potent TLR1/2 agonist(EC50 of 52.9 nM in HEK-Blue hTLR2 SEAP assay). It acts by activating the NFkB pathway, upregulating proinflammatory cytokines, and enhancing TLR1 and TLR2 dimerization.CU-T12-9 activates both the innate and the adaptive immune systems. CU-T12-9 selectively activates the TLR1/2 heterodimer, not TLR2/6. CU-T12-9 signals through NF-κB and invokes an elevation of the downstream effectors TNF-α, IL-10, and iNOS.

Manumycin A is an antibiotic with anticancer activity and is a mammalian thioredoxin reductase-1 (TrxR-1) inhibitor.Manumycin A inhibits the production of IL-1β, IL-6, and IL-8 in TNF alpha-stimulated THP-1 cells and peripheral blood mononuclear cells in a dose-dependent manner, inducing apoptosis.

Sabialimon P (compound 16), with an IC50 of 18.12 μM, functions as a NO release inhibitor and exhibits anti-inflammatory properties. It effectively diminishes the secretion of TNF-α, iNOS, IL-6, and NF-κB, and suppresses the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells.

PDE1-IN-9 (Compound 7a) is a selective inhibitor of phosphodiesterase 1 (PDE1), targeting PDE1C with an IC50 value of 11 nM. It effectively reduces the mRNA expression of IL-1β, IL-6, TNF-α, and iNOS, while also inhibiting the production of nitric oxide (NO) and reactive oxygen species (ROS). Additionally, PDE1-IN-9 demonstrates good metabolic stability in rat liver microsomes.

COX-2/15-LOX-IN-6 (Compound 5l) is a dual inhibitor of COX-2 and 15-LOX with IC50 values of 0.201 μM and 11.723 μM, respectively. In serum, it suppresses the expression of PGE, TNF-α, IL-6, and iNOS, and demonstrates anti-inflammatory activity in a carrageenan-induced rat edema model.

CB2 receptor agonist 9 (Compound 33) is an orally active agonist of cannabinoid receptor 2 (CB2 receptor) with an EC50 of 16.2 nM. It inhibits the expression of TNF-α, IL-1β, and IL-6, demonstrating anti-inflammatory activity in a DSS-induced acute colitis model in mice.

SDMA p-Hydroxyazobenzene-p′-sulfonate is the p-hydroxyazobenzene-p′-sulfonate form of SDMA. It acts as an inhibitor of endogenous nitric oxide synthase (NO synthase) and serves as an activator of NF-κB, enhancing the expression of IL-6 and TNF-α. This compound remains stable in serum and plasma, making it a potential biomarker for liver and kidney dysfunction.

NF-κB/MAPK-IN-2 (compound 14) is a potent inhibitor of NF-κB and MAPK pathways. It effectively reduces the protein expression levels of p-p65, p-IκB, p-p38, p-JNK, and p-ERK. This compound decreases the release of TNF-α and IL-6 induced by LPS and inhibits the nuclear translocation of p65 and c-Fos. NF-κB/MAPK-IN-2 shows potential for research in sepsis.

HDAC6degrader-5 (Compound 6) exhibits inhibitory and degradative activity against HDAC6, with an IC50 of 4.95 nM and a DC50 of 0.96 nM. It suppresses the release of TNF-α, IL-1β, and IL-6, and prevents apoptosis in liver cells. Additionally, HDAC6degrader-5 demonstrates anti-inflammatory properties in a mouse model of APAP-induced liver injury.

EGFR-IN-144 (Compound 4B) inhibits EGFR (IC50=0.639 µg/mL) and tubulin polymerization (IC50=7.339 µg/mL). It exhibits cytotoxicity in various cancer cells with a GI50 at the nanomolar level. EGFR-IN-144 reduces the expression of mTOR, TNF-α, and IL-6, causes G1/S phase cell cycle arrest, and induces apoptosis.

Keap1-Nrf2-IN-27 is an inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI) with a KD2 value of 0.119 μM. It suppresses the expression of pro-inflammatory cytokines TNF-α and IL-6 in an LPS-induced RAW264.7 cell model.

5-LOX-IN-8 is a 5-LOX inhibitor with anti-inflammatory properties. It suppresses IL-6, IL-1β, TNF-α, and IFN-γ in macrophages and reduces IL-8 secretion in SW480 cells. Additionally, 5-LOX-IN-8 decreases the disease activity index in DSS colitis models. This compound is applicable for research in inflammatory bowel disease (IBD).

SMU-14a is a TLR3 inhibitor with an IC50 of 0.18 µM. It suppresses IL-6 secretion in mouse peritoneal macrophages and downregulates TNF-α in human peripheral blood mononuclear cells. The compound exerts anti-inflammatory effects by reducing the phosphorylation of p65, ERK, and TBK1 via the NF-κB, MAPK, and IRF3 signaling pathways, and by lowering serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). SMU-14a is applicable in acute hepatitis research.

BS-153 is a novel synthetic oxazolidinone drug that exhibits anti-inflammatory effects by blocking the activation of the NF-κB/PKCθ pathway. It can suppress the expression levels of iNOS, COX-2, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in LPS-stimulated RAW264.7 cells.

SARS-CoV-2 Mpro-IN-41 (Compound 7e) is an orally active inhibitor targeting COX-2 and SARS-CoV-2 Mpro, with respective IC50 values of 9.66 μM and 13.24 μM. It also demonstrates inhibitory activity against COX-1 (IC50: 46.11 μM). This compound significantly suppresses the expression of inflammation-related cytokines such as TNF-α, IL-6, and IL-1β, exhibiting anti-inflammatory properties. By selectively inhibiting COX-2 and SARS-CoV-2 Mpro, SARS-CoV-2 Mpro-IN-41 exerts both anti-inflammatory and antiviral effects, making it a potential candidate for research in inflammation and COVID-19 treatment.

12-Nitrolinoleate is a linoleic acid derivative that acts as an agonist of peroxisome proliferator-activated receptor γ (PPARγ). Formed via exposure to acidified nitrite, it is present in human red blood cells and plasma. This compound stimulates PPARγ-dependent gene expression, demonstrated in a reporter assay with MCF-7 cells expressing human PPARγ, with an EC50 of 0.045 µM. At 2.5 µM, 12-Nitrolinoleate reduces the secretion of IL-6, TNF-α, and chemokine (C-C motif) ligand 2 (CCL2) in THP-1 and RAW 264.7 macrophages, and it suppresses LPS-induced NF-κB transcriptional activity in RAW 264.7 macrophages. Additionally, it inhibits TNF-α-induced increases in vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and enhances heme oxygenase-1 (HO-1) levels in primary human aortic endothelial cells at concentrations of 1, 5, or 10 µM.