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In order to discover novel anti-inflammatory agents, total thirty-seven new resveratrol-based flavonol derivatives were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Their toxicity was also assessed in vitro. Structure-activity relationships (SARs) have been concluded, and finally 2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-4H-chromen-4-one was found to be the most active scaffold with low toxicity. This compound could significantly decrease productions of NO, IL-6 and TNF-α with IC 50 values of 1.35, 1.12 and 1.92 μM, respectively in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein, resulting in activation of the NF-ĸB cell signaling pathway. The in vivo anti-inflammatory activity of this compound could reduce pulmonary inflammation by mouse model of LPS-induced acute lung injury (ALI). We believe these findings would further support studies of rational design of more efficient acute lung injury regulatory inhibitors. New resveratrol-based flavonol derivatives with anti-inflammatory were synthesized. Among them, one compound could significantly decreased production of NO, IL-6 and TNF-α LPS-stimulated. Preliminary mechanism indicated that it could inhibit expression of TLR4, resulting in activation cell signaling pathway NF-ĸB and MAPK. The in vivo anti-inflammatory activity was determined by LPS-induced acute lung injury. Image 1 • Novel resveratrol-based flavonol compounds were synthesized. • Compound showed high anti-inflammatory activity against IL-6、NO and TNF-α. • Preliminary mechanisms of anti-inflammatory action were discovered. [ABSTRACT FROM AUTHOR]

To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives ( 4a ∼ 4m ) were designed and synthesized. Compounds 4a and 4b were determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-α, NO through NF-κB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints. [ABSTRACT FROM AUTHOR]

Based on telomerase, thirteen novel phenstatin moiety linked stavudine derivatives ( 8a ∼ 8e and 11a ∼ 11f ) were synthesized. The structures were determined by NMR and TOF-HRMS. The screening results showed that some compounds had better anti-cancer activity in vivo and in vitro . Among them, Compound 8d showed high inhibitory activity against telomerase and showed good antiproliferative activity against SGC-7901 cell with IC 50 value 0.77 μM by inducing cell cycle arrest at G2 phase. It also could improve SGC-7901 cell apoptosis, mitochondrial membrane potential assay indicated that the dissipation of MMP might participate in apoptosis induced by title compound. In vivo studies showed that compound 8d displayed potent anticancer activity with inhibition tumor growth. [ABSTRACT FROM AUTHOR]

In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on "Hit" we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3- d ]pyrimidine and thieno[3,2- d ]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC 50 = 2934, 2301 μM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 μM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC 50 is 0.96 μM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo , acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment. Image 1 • New pyrazolo/thieno-fused pyrimidine derivatives were designed and synthesized. • Clear relationships of balance toxicity and activity were summarized. • Preliminary mechanism against iNOS were discussed. [ABSTRACT FROM AUTHOR]

Phthalide is a promising chemical scaffold and has been proved to show potent anti-inflammatory efficacy. In this study, three series, total of 31 novel phthalide derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. The anti-inflammatory activity of all the compounds were screened on LPS induced NO production to evaluating their inhibitory effects. Structure-activity relationship has been concluded, and finally 3-((4-((4-fluorobenzyl)oxy)phenyl)(hydroxy)methyl)-5,7-dimethoxyisobenzofuran-1 (3H)-one (compound 9o) was found to be the active one with low toxicity, which showed 95.23% inhibitory rate at 10 μM with IC 50 value of 0.76 μM against LPS-induced NO over expression. Preliminary mechanism studies indicated that compound 9o activated Nrf2/HO-1 signaling pathway via accumulation ROS and blocks the NF-κB/MAPK signaling pathway. The in vivo anti-inflammatory activity shown that compound 9o had obvious therapeutic effect against the adjuvant-induced rat arthritis model. Image 1 • Novel phthalide derivatives were designed and synthesized. • In vivo studies showed that title compound had good therapeutic effect. • Preliminary mechanisms of anti-inflammatory action were discovered. [ABSTRACT FROM AUTHOR]

NLRP3 inflammasome activation plays a key role in a variety of inflammatory diseases as IBD. Here a series of pterostilbene derivatives were designed and synthesized based on previous SAR, leading to discovery of new effective NLRP3 inflammasome inhibitors with metabolic stability. Among them, the most effective compound 27 showed high inhibitory efficacy (against IL-1 β: IC 50 = 1.23 μM) and almost no toxicity (against L02: IC 50 > 100 μM). Further mechanism studies have shown that compound 27 directly targets the NLRP3 and affects the assembly of inflammasomes to inhibit the activation of NLRP3 inflammasomes. More importantly, in vitro experiments show that compound 27 has a significant therapeutic effect on DSS-induced colitis in mice with good metabolic stability to liver microsomes (t 1/2 = 138.6 min). This research encourages the further development of more effective NLRP3 inflammasome inhibitors based on this chemical scaffold. [Display omitted] • New NLRP3 inflammasome inhibitors were designed and synthesized. • The structure-based optimization and SAR study were fully carried out. • Further mechanism studies indicated it affected the assembly of inflammasomes. [ABSTRACT FROM AUTHOR]