Furo[3′,2′:3,4]naphtho[1,2-d

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• 作者：Chih-Hua Tseng ; Chang-Sheng Lin ; Pin-Keng Shih ; Lo-Ti Tsao ; Jih-Pyang Wang ; Chih-Mei Cheng ; Cherng-Chyi Tzeng ; Yeh-Long Chen
• 关键词：Furo[3′ ; 2′ ; 3 ; 4]naphtho[1 ; 2-d]imidazole ; Anti-inflammatory ; Nitric oxide ; Inducible nitric ; Oxide synthase ; Sepsis
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：15 September 2009
• 年：2009
• 卷：17
• 期：18
• 页码：6773-6779
• 全文大小：458 K

文摘

Synthesis and anti-inflammatory effects of certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives 12–18 were studied. These compounds were synthesized from naphtho[1,2-b]furan-4,5-dione (10) which in turn was prepared from the known 2-hydoxy-1,4-naphthoquinone (7) in a one pot reaction. Furo[3′,2′:3,4]naphtho[1,2-d]imidazole (12) was inactive (IC₅₀ value of >30 μM) while its 5-phenyl derivative 13, with an IC₅₀ value of 16.3 and 11.4 μM against lysozyme and β-glucuronidase release, respectively, was comparable to the positive trifluoperazine. The same potency was observed for 5-furan derivative 16 with an IC₅₀ value of 19.5 and 11.3 μM against lysozyme and β-glucuronidase release, respectively. An electron-withdrawing NO₂ substituted on 5-phenyl or 5-furanyl group led to the devoid of activity as in the cases of 14 and 17. Among them, compound 15 exhibited significant inhibitory effects, with an IC₅₀ value of 7.4 and 5.0 μM against lysozyme and β-glucuronidase release, respectively.

For the LPS-induced NO production, the phenyl derivatives 12–15 were inactive while the nitrofuran counterparts 17 and 18 suppress LPS-induced NO production significantly, with an IC₅₀ value of 1.5 and 1.3 μM, respectively, which are more active than that of the positive 1400 W. Compounds 16–18 were capable of inhibiting LPS-induced iNOS protein expression at a dose-dependent manner in which compound 18, with an IC₅₀ of 0.52 μM in the inhibition of iNOS expression, is approximately fivefold more potent than that of the positive 1400 W. In the CLP rat animal model, compound 18 was found to be more active than the positive hydrocortisone in the inhibition of the iNOS mRNA expression in rat lung tissue. The sepsis-induced PGE2 production in rat serum decreased 150 % by the pretreatment of 18 in a dose of 10 mg/kg.