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-1β, 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.
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 (IC 50 = 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.
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.
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