Discovery of Coixol Derivatives as Potent Anti-inflammatory Agents.

Coixol, a derivative of 2-benzoxazolinone extracted from coix (Coix lachryma-jobi L. var. ma-yuen Stapf), has demonstrated promising anti-inflammatory activity and low cytotoxicity. In this study, 26 coixol derivatives were designed and synthesized by hybridization with cinnamic acid to identify new anti-inflammatory agents. The anti-inflammatory activities of the derivatives were screened using LPS-induced overexpression of nitric oxide (NO) in RAW264.7 macrophages. On the basis of the screening results, compounds containing furan (9c) or nitrofuran (9j) moieties displayed more pronounced activity than coixol and celecoxib. Mechanistic investigations revealed that 9c and 9j suppressed the expression of induced nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß, which was associated with the inhibition of the nuclear factor (NF)-κB signaling pathway. In vivo studies confirmed the anti-inflammatory activity of 9c and 9j in a xylene-induced mice auricles edema model. The preliminary in vitro and in vivo research findings suggest that 9c and 9j have the potential to be developed as anti-inflammatory agents.

Terazosin Analogs Targeting Pgk1 as Neuroprotective Agents: Design, Synthesis, and Evaluation.

Nitrogen-containing heterocyclic compounds have shown promising therapeutic effects in a variety of inflammatory and neurodegenerative diseases. Recently, terazosin (TZ), a heterocyclic compound with a quinazoline core, was found to combine with phosphoglycerol kinase 1 (Pgk1) and protect neurons by enhancing Pgk1 activity and promoting glycolysis, thereby slowing, or preventing the neurodegeneration of PD. These findings indicated that terazosin analogs have bright prospects for the development of PD therapeutics. In this study, a series of terazosin analogs were designed and synthesized for neuroprotective effects by targeting Pgk1. Among them, compound 12b was obtained with the best Pgk1 agonistic activity and neuroprotective activity. Further study indicates that it can increase intracellular ATP content and reduce ROS levels by stimulating the activity of Pgk1, thereby playing a role in protecting nerve cells. In conclusion, this study provides a new strategy and reference for the development of neuroprotective drugs.

Design and synthesis of novel indole and indazole-piperazine pyrimidine derivatives with anti-inflammatory and neuroprotective activities for ischemic stroke treatment.

Microglia-mediated neuroinflammation plays an important role in ischemic stroke (IS). In this work, a series of novel indole and indazole-piperazine pyrimidine derivatives with anti-neuroinflammatory and neuroprotective activities were designed and synthesized for treatment of IS. Among these compounds, 5j displayed the most attractive cytoprotective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage in BV2 cells. Meanwhile, it significantly ameliorated the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, nitric oxide (NO) and prostaglandin E2 (PGE2), from lipopolysaccharide (LPS)-induced BV2 cells. Moreover, 5j can decrease the release of TNF-α and IL-1ß form LPS-induced mouse brain neuroinflammation model. As a potent inhibitor against both cyclooxygenase-2 (COX-2, IC50 = 92.54 nM) and 5-lipoxygenase (5-LOX, IC50 = 41.86 nM), 5j inhibited the M1 phenotype polarization of microglia and promoted the M2 phenotype polarization of microglia. Additionally, 5j exhibited remarkable neuroprotection in middle cerebral artery occlusion (MCAO) rats by reducing their infarct volumes and neurological deficit scores. In conclusion, 5j has the potential for the treatment of stroke as an anti-inflammatory and neuroprotective agent.

Hybrids of aurantiamide acetate and isopropylated genipin as potential anti-inflammatory agents: The design, synthesis, and biological evaluation.

A novel series of hybrids designed on the basis of aurantiamide acetate and isopropylated genipin were synthesized and biologically evaluated as anti-inflammatory agents. Among them, compound 7o exhibited the best inhibitory activity against TNF-α secretion (IC50  = 16.90 µM) and was selected for further in vitro and in vivo functional study. The results demonstrated that 7o was capable of suppressing the expression of LPS-induced iNOS and COX-2, as well as reducing the production of NO at the concentration of 5 µM, which may be resulted from its regulation of NF-κB signaling and MAPK signaling. Moreover, compound 7o exhibited favorable in vivo anti-inflammatory activity with an inhibition rate of 53.32% against xylene-induced ear swelling in mice at the dose of 5 mg/kg.