Synthesis and biological activity of new phthalimides as potential anti-inflammatory agents. Issue 13 (1st July 2017)

• Record Type: Journal Article
• Authors: Bach, Duc-Hiep; Liu, Jian-Yu; Kim, Won Kyung; Hong, Ji-Young; Park, So Hyun; Kim, Donghwa; Qin, Si-Ning; Luu, Thi-Thu-Trang; Park, Hyen Joo; Xu, Yong-Nan; Lee, Sang Kook
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 13(2017)
• Page Start: 3396
• Page End: 3405
• Publication Date: 2017-07-01
• Subjects: Phthalimides -- Anti-inflammation -- iNOS -- Toll-like receptor (TLR) 4; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.027
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: New series of phthalimides were synthesized including the C7-alkyl chain as a key finding and structure-activity study with the inhibition of nitric oxide production was investigated. Abstract: The overproduction of nitric oxide (NO) plays an important role in a variety of pathophysiological processes, including inflammation. Therefore, the suppression of NO production is a promising target in the design of anti-inflammatory agents. In the present study, a series of phthalimide analogs was synthesized, and their anti-inflammatory activities were evaluated using lipopolysaccharide (LPS)-stimulated NO production in cultured murine macrophage RAW264.7 cells. A structure-activity relationship study showed that the free hydroxyl group at C-4 and C-6 and the bulkiness of the N -substituted alkyl chain are associated with biological activity. Among the series of phthalimide derivatives, compoundIIh exhibited potent inhibitory activity, with an IC50 value of 8.7 µg/mL. Further study revealed that the inhibitory activity of compoundIIh was correlated with the down-regulation of the mRNA and protein expression of LPS-stimulated inducible nitric oxide synthase (iNOS). CompoundIIh also suppressed the induction of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β in LPS-stimulated RAW 264.7 cells. The anti-inflammatory activity of compoundIIh was also found to be associated with the suppression of the Toll-like receptor (TLR)4 signaling pathway by down-regulating the activation of interferon regulatory factor 3 (IRF-3) and interferon-β and signal transducer expression. These findings demonstrate that novel phthalimides might be potential candidates for the development of anti-inflammatory agents.