2. Academic Validation
  3. Repurposing mosloflavone/5,6,7-trimethoxyflavone-resveratrol hybrids: Discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators

Repurposing mosloflavone/5,6,7-trimethoxyflavone-resveratrol hybrids: Discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators

  • Eur J Med Chem. 2019 Oct 15;180:253-267. doi: 10.1016/j.ejmech.2019.07.030.
Ahmed H E Hassan 1,  Sung Yeun Yoo 2,  Kun Won Lee 2,  Yoon Mi Yoon 2,  Hye Won Ryu 2,  Youngdo Jeong 2,  Ji-Sun Shin 3,  Shin-Young Kang 4,  Seo-Yeon Kim 4,  Hwi-Ho Lee 4,  Boyoung Y Park 5,  Kyung-Tae Lee 4,  Yong Sup Lee 6
Affiliations

Affiliations

  • 1 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea.
  • 2 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea.
  • 3 Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 4 Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 6 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea. Electronic address: kyslee@khu.ac.kr.
PMID: 31310917 DOI: 10.1016/j.ejmech.2019.07.030
Abstract

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from Anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 μM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE2, IL-6, TNF-α and IL-1β. Compound 5z inhibited the induced production of NO, PGE2, IL-6, TNF-α and IL-1β at the low 1 μM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC50 values as low as 2.11 and 0.98 μM against NO and PGE2 production respectively. Compounds 5q and 5g showed potent submicromolar IC50 values of 0.31 and 0.59 μM respectively against PGE2 production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.

Keywords

Anti-inflammatory; Flavones; Hybrid molecules; IL-1β; IL-6; Macrophages; Natural products-based drug discovery; Nitric oxide; PGE(2); Repurposing; Resveratrol; TNF-α; p38-α inhibitors.

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