- Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer
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Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (9a-f) or hippuric (11a,b) acid moieties linked to 2-
- Abdel-Aziz, Hatem A.,Al-Sanea, Mohammad M.,Al-Warhi, Tarfah,Aljaeed, Nada,Alotaibi, Ohoud J.,Eldehna, Wagdy M.,Elsayed, Zainab M.,Nocentini, Alessio,Supuran, Claudiu T.
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- Quantum reality in the selective reduction of a benzofuran system
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Two 2,3-disubstituted benzofurans (1 and 2), analogs of gamma-aminobutyric acid (GABA), were synthesized to obtain their 2,3-dihydro derivatives from the Pd/C-driven catalytic reduction of the double bond in the furanoid ring. The synthesis produced surprising by-products. Therefore, theoretical calculations of global and local reactivity were performed based on Pearson's hard and soft acids and bases (HSAB) principle to understand the regioselectivity that occurred in the reduction of the olefinic carbons of the compounds. Local electrophilicity (ωk) was the most useful parameter for explaining the selectivity of the polar reactions. This local parameter was defined with the condensed Fukui function and redefined with the electrophilic (Pk+) Parr function. The similar patterns of both resulting sets of values helped to demonstrate the electrophilic behavior (soft acid) of the olefinic carbons in these compounds. The theoretical calculations, nuclear magnetic resonance, and resonance hybrids showed the moieties in each compound that are most susceptible to reduction.
- Coaviche-Yoval, Arturo,Andrade-Jorge, Erik,Pérez-González, Cuauhtémoc,Luna, Héctor,Tovar-Miranda, Ricardo,Trujillo-Ferrara, José G.
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- Development of novel benzofuran-based SLC-0111 analogs as selective cancer-associated carbonic anhydrase isoform IX inhibitors
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In the present study, we describe the design of different series of benzofuran-based derivatives as potential carbonic anhydrase inhibitors (CAIs). The adopted design is based on bioisosteric replacement for the p-fluorophenyl SLC-0111 tail with the lipop
- Shaldam, Moataz,Eldehna, Wagdy M.,Nocentini, Alessio,Elsayed, Zainab M.,Ibrahim, Tamer M.,Salem, Rofaida,El-Domany, Ramadan A.,Capasso, Clemente,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
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- Synthesis, SAR, molecular docking and antituberculosis study of 3-methyl-1-benzofuran-2-carbohydrazide
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3-Methyl-1-benzofuran-2-carbohydrazide was synthesized from 2-hydroxy acetophenone. To deduce the antibacterial and anticancer activity of the 3-methyl-1-benzofuran-2-carbohydrazide, it is docked with different biomarkers of cancer cell and bacteria. The
- Thorat, Bapu R.,Nazirkar, Bhusan,Thorat, Vaishali B.,More, Kishor,Jagtap, Ravindra,Yamgar, Ramesh
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- Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer
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In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a–e and 7a–i) was designed and synthesised. The anticancer activity for compounds (5b–d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a–e and 7a–i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC50 = 8.7 and 9.4 μM (5a), and 6.5 and 9.8 μM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.
- Eldehna, Wagdy M.,Salem, Rofaida,Elsayed, Zainab M.,Al-Warhi, Tarfah,Knany, Hamada R.,Ayyad, Rezk R.,Traiki, Thamer Bin,Abdulla, Maha-Hamadien,Ahmad, Rehan,Abdel-Aziz, Hatem A.,El-Haggar, Radwan
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p. 1424 - 1435
(2021/07/02)
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- Discovery of a promising agent IQZ23 for the treatment of obesity and related metabolic disorders
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Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel β-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC50 = 0.033 μM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders.
- Chen, Shuo-Bin,Hu, Yu-Tao,Huang, Shi-Liang,Huang, Zhi-Shu,Li, Chan,Li, Qing-Jiang,Ou, Tian-Miao,Rao, Yong,Song, Bing-Bing,Song, Qin-Qin,Tan, Jia-Heng,Wang, Hong-Gen,Xu, Yao-Hao,Xu, Zhao,Ye, Ji-Ming,Yu, Hong,Zhong, Guo-Ping
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- 4-Hydroxy-3-methylbenzofuran-2-carbohydrazones as novel LSD1 inhibitors
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Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC50 values ranging from 7.2 to 68.8 nM. In cellular assays, several compounds inhibited the proliferations of various cancer cell lines, including PC-3, MCG-803, U87 MG, PANC-1, HT-29 and MCF-7. This opens up the opportunity for further optimization and investigation of this class compounds for potential cancer treatment.
- Gao, Yuan,He, Xingrui,Hui, Zi,Shen, Guodong,Wang, Shuo,Xie, Tian,Ye, Xiang-Yang
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- Discovery and Development of a Series of Pyrazolo[3,4- d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design
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Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scorin
- Wang, Yulan,Dai, Yang,Wu, Xiaowei,Li, Fei,Liu, Bo,Li, Chunpu,Liu, Qiufeng,Zhou, Yuanyang,Wang, Bao,Zhu, Mingrui,Cui, Rongrong,Tan, Xiaoqin,Xiong, Zhaoping,Liu, Jia,Tan, Minjia,Xu, Yechun,Geng, Meiyu,Jiang, Hualiang,Liu, Hong,Ai, Jing,Zheng, Mingyue
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p. 7473 - 7488
(2019/09/03)
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- Synthesis and biological evaluation of novel 2,3-disubstituted benzofuran analogues of GABA as neurotropic agents
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Background: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. Objective: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. Methods: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. Results: The tested ligands that complied with Lipinski’s rule of five were tested in silico with GABAA-R (δG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, δG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7percent). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. Conclusion: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.
- Coaviche-Yoval, Arturo,Luna, Héctor,Soriano-Ursúa, Marvin A.,Tovar-Miranda, Ricardo,Trujillo-Ferrara, José G.
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- New One-Pot Synthesis of Polysubstituted Benzofurans and Benzo-1,4-dioxines
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It has been revealed that the copper(II) triflate catalyzed reaction of ethyl-2-diazo-3-oxobutanoate with phenols followed by cyclization of the intermediate enol in the presence of polyphosphoric acid is a simple and efficient method of synthesis of polysubstituted benzofurans. The use of pyrocatechol leads to the corresponding substituted 1,4-benzodioxine-2-carboxylates as major products.
- Sakhabutdinova,Raskil’dina,Zlotskii,Sultanova
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p. 233 - 236
(2018/11/21)
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- Efficient synthesis of chiral benzofuryl β-amino alcohols via a catalytic asymmetric Henry reaction
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Chiral β-amino alcohol ligands were found effective for the copper(ii)-catalyzed asymmetric Henry reaction of benzofuran-2-carbaldehydes with nitromethane, which led to the formation of (S)-enriched benzofuryl β-nitro alcohols with satisfactory enantioselectivities (up to 98% ee). Using this catalytic protocol, bioactive (S)-benzofuryl β-amino alcohols could be conveniently prepared in short steps.
- Chen, Wei,Zhou, Zhao-Hui,Chen, Hong-Bin
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supporting information
p. 1530 - 1536
(2017/02/15)
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- Substrate-Tuned Catalysis of the Radical S-Adenosyl- L -Methionine Enzyme NosL Involved in Nosiheptide Biosynthesis
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NosL is a radical S-adenosyl-L-methionine (SAM) enzyme that converts L-Trp to 3-methyl-2-indolic acid, a key intermediate in the biosynthesis of a thiopeptide antibiotic nosiheptide. In this work we investigated NosL catalysis by using a series of Trp analogues as the molecular probes. Using a benzofuran substrate 2-amino-3-(benzofuran-3-yl)propanoic acid (ABPA), we clearly demonstrated that the 5′-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction in NosL catalysis is not from the indole nitrogen but likely from the amino group of L-Trp. Unexpectedly, the major product of ABPA is a decarboxylated compound, indicating that NosL was transformed to a novel decarboxylase by an unnatural substrate. Furthermore, we showed that, for the first time to our knowledge, the dAdo radical-mediated hydrogen abstraction can occur from an alcohol hydroxy group. Our study demonstrates the intriguing promiscuity of NosL catalysis and highlights the potential of engineering radical SAM enzymes for novel activities.
- Ji, Xinjian,Li, Yongzhen,Ding, Wei,Zhang, Qi
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p. 9021 - 9024
(2015/08/03)
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- Facile microwave-assisted synthesis of substituted benzofuran derivatives
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A series of benzofuran derivatives have been synthesized by use of a microwave-assisted process. Substituted or unsubstituted ?- hydroxyacetophenone and salicylaldehyde reacted with ethyl bromoacetate, ω-bromoacetophenone, or chloroacetone under the action of potassium carbonate in DMF to yield substituted benzofuran derivatives. Compared with conventional heating, this microwave-assisted synthetic process has the advantages of more convenient operation, shorter reaction time, and higher yield.
- Liu, Junqiang,Mi, Chenggen,Tang, Xuemei,Cao, Yuan,Li, Zicheng,Huang, Wencai
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p. 2083 - 2090
(2014/05/06)
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- Synthesis, antiproliferative activities and in vitro biological evaluation of novel benzofuransulfonamide derivatives
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In a cell-based screen of novel antiproliferative agents, the hit compound 1a, which bears a benzofuransulfonamide scaffold, exhibited broad-spectrum antiproliferative activities against a panel of tumor cell lines. The promising in vitro antiproliferative activity and structural novelty of 1a prompted us to investigate the synthesis of five analogs of 1a and test their antiproliferative activities. The most potent analogue, 1h, exhibited enhanced antiproliferative activities compared with the parent 1a, and exhibited an IC50 value against NCI-H460 cells of 4.13 μM compared with 4.52 μM for the positive control cisplatin. Flow cytometric analysis revealed that 1h induces significant levels of apoptosis in NCI-H460 cells in vitro at low micromolar concentrations. These results suggest that 1a and analogs based on its benzofuransulfonamide scaffold may constitute a novel class of antiproliferative agents, which deserve further study.
- Yang, Li,Lei, Hua,Mi, Cheng-Gen,Liu, Huan,Zhou, Tian,Zhao, Ying-Lan,Lai, Xiao-Yun,Li, Zi-Cheng,Song, Hang,Huang, Wen-Cai
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supporting information; scheme or table
p. 5389 - 5392
(2011/10/12)
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- Syntheses and pyrolyses of benzofuran analogues of α-oxo-o- quinodimethane. A study on vinylcarbene-cyclopropene rearrangement
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(Chemical Equation Presented) Flash vacuum pyrolyses (FVP) of benzoic 3-methyl-2-benzofurancarboxylic anhydride (12) and benzoic 2-methyl-3- benzofurancarboxylic anhydride (13) at 550°C and ca. 10-2 torr both give methylenebenzocyclobutenone (21) as the major product and indenone (22) as the minor one. A mechanism involving generation of α-oxo-o- quinodimethane 11 as the primary pyrolysis product from FVP of 13, followed by elimination of a CO molecule to give carbene 24, which undergoes a vinylcarbene-cyclopropene rearrangement and a ring contraction of the resulting carbene 23, is proposed to account for the observed results. The proposed mechanism is further supported by a deuterium-labeling study on FVP of (2-benzofuryl)methyl-α,α-d2 benzoate (28-d2).
- Tseng, Pen-Wen,Yeh, Su-Wen,Chou, Chin-Hsing
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p. 3481 - 3485
(2008/09/21)
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- Ambient temperature method for the generation and Diels-Alder trapping of benzofuran-2,3-quinodimethane (2,3-dimethylidene-2,3-dihydrobenzofuran)
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The Ito-Saegusa method has been used to generate benzofuran-2,3-quinodimethane 10 from the corresponding silyl acetate 17b in solution at -4°C. The intermediate reacts efficiently with a range of reactive Diels-Alder dienophiles with moderate to good levels of regioselection; the structure of the major diastereoisomer has been determined by X-ray analysis.
- Bedford, Simon B.,Begley, Michael J.,Cornwall, Philip,Foreman, Joel P.,Knight, David W.
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p. 2827 - 2832
(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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