- Design and synthesis of novel 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives as potent Mnks inhibitors by fragment-based drug design
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A novel series of 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives featured with various C-2 substituents were designed and synthesized as Mnks inhibitors through fragment-based drug design. Among them, 5b, 5i, 5o and 8k showed the best Mnk2 inhibitory activity with IC50 values of 1.45, 1.16, 3.55 and 0.27 μM, respectively. And these compounds inhibited the activity of Mnk1 at the same time. Furthermore, compounds 5o and 8k exhibited anti-proliferative effects to human leukemia cancer THP-1 and MOLM-13 cell lines and colon cancer HCT-116 cell line. Moreover, Western blot assay suggested that 8k could decrease the levels of p-eIF4E in a dose-dependent manner in HCT-116 cells. Docking studies demonstrated strong interactions between 8k and Mnk2. Therefore, this unique benzofuran scaffold demonstrated great potential to be further explored as potent Mnks inhibitors with improved potency.
- Wang, Shuxiang,Li, Bo,Liu, Bo,Huang, Min,Li, Deyi,Guan, Lihong,Zang, Jie,Liu, Dan,Zhao, Linxiang
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- Expedited synthesis of benzofuran-2-carboxylic acids via microwave-assisted Perkin rearrangement reaction
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3-Halocoumarins are readily converted into benzofuran-2-carboxylic acids via a Perkin (coumarin-benzofuran ring contraction) rearrangement reaction. This rearrangement entails initial base catalyzed ring fission. The resulting phenoxide anion then attacks a vinyl halide to produce the final benzofuran moiety. We explored this reaction under microwave reaction conditions and were able to significantly reduce reaction times as well as obtain very high yields of a series of benzofuran-2-carboxylic acid derivatives.
- Marriott, Karla-Sue C.,Bartee, Rena,Morrison, Andrew Z.,Stewart, Leonard,Wesby, Julian
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- Synthesis, pharmacological studies and molecular modeling of some tetracyclic 1,3-diazepinium chlorides
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Seven new 1,3-diazepinium chlorides exhibiting some structural similarities to the 1,4-benzodiazepines were synthesized. In a Hippocratic screen using mice, three of these salts, 3-methoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8a), 3-methoxy-9-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8c) and 3-methoxy-11-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8e) were examined for their effect on the central nervous system, and their activities compared to that of diazepam. On their own, salts 8a, 8c and 8e solicited no sedative effects on the behaviour of the animals. However, they elicited significant effects in combination with diazepam on diazepam-induced activities such as decreased motor activity, ataxia and loss of righting reflex. Compounds 8a and 8c were fitted into the pharmacophore/receptor model developed by Cook et al. with interaction at the L1, H1 and A2 sites indicating that they are potential inverse agonists of the Bz receptor. The compounds displayed some affinity for the α1 isoform of the GABAA/BzR (LDi interaction) but are non-selective for α5 (no L2 interaction). Results of binding affinity studies showed that compound 8a is mildly selective for the α1 receptor although not very potent (Ki = 746.5 nM). The significant potentiation of diazepam-induced ataxia and decreased motor activity by compounds 8a and 8c in the Hippocratic screen may be associated with α1 selectivity.
- Grant, Julie-Ann A.,Bonnick, Tamicka,Gossell-Williams, Maxine,Clayton, Terry,Cook, James M.,Jackson, Yvette A.
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- A convenient procedure for the synthesis of substituted 4-methylaminocoumarins
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3-Bromo-7-methoxy-4-methylcoumarin and 3-bromo-4,7-dimethyl-coumarin give a mixture of the corresponding 3-aminocoumarins and 4-aminomethylcoumarins upon the reaction with a number of secondary amines. In addition, the reaction of 7-methoxy- and 7-methyl-4-bromomethylcoumarins with secondary diamines affords the corresponding, N,N-dicoumarinmethyldiamine.
- Al-Zghoul, Khadeejh H.,Salih, Kifah S.M.,Ayoub, Mikdad T.,Mubarak, Mohammad S.
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- Heterocycles from 2-aminopyridine and derivatives of 3-methylbenzofuran-2-carboxylic acid
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3-Bromomethyl-2-carboethoxy-5,6-dimethoxybenzofuran (3b) reacted with 2-aminopyridine to give not only the expected 2-carboethoxy-5,6-dimethoxy-3-benzofuranmethyl-2′-aminopyridinium bromide (4b), but also N-(2-carboethoxy-5,6-dimethoxy-3-benzofuranmethyl)-N-2-pyridyl-amine (5). Synthesis of 3-methoxy-6,7,12-trihydro-6-oxo-[1]benzofurano-[2,3-c]-1H-pyrido[1,2-a][1,3] diazepinium bromide (1 2) is also described.
- Jackson, Yvette A.,Williams, Mark F.
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p. 787 - 794
(2007/10/03)
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- Benzofuran Derivatives. Part 4. Synthesis of Benzofurans and 2,3,4,5-Tetrahydro-1-benzoxepin-3,5-diones
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By treatment of ethyl 4- or 5-substituted 2-acetylphenoxyacetates 1 with potassium hydroxide in dry dioxane, benzofurans 2-7 and 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones 8 were obtained.The relative yields of benzofurans 2-7 and 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones 8 varied with the types of 4- or 5-substituents.The electron-donating 4-methoxyl group favored the formation of benzoxepins.On the other hand, electron-withdrawing substituents such as the 4-nitro group favored the formation of benzofurans.When esters 1 were treated with sodium amide,2,3-dihydrobenzofurans 2 were obtained exclusively regardless of 4- or 5-substituents.
- Suzuki, Tsuneo,Tanemura, Kiyoshi,Horaguchi, Takaaki,Shimimizu, Takahachi,Sakakibara, Tohru
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p. 423 - 429
(2007/10/02)
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