- Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants
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A series of coumarin derivatives 6–8, 9a-h, 11 and 13a, b -16a, b was synthesized and screened for their anticonvulsant profile. Screening of these analogues using the 'gold standard methods' revealed variable anticonvulsant potential with remarkable effects observed particularly in chemically-induced seizure test. Compounds 6, 7, 13b disclosed the highest potency among the series with 100% protection against scPTZ. Quantification study confirmed that compound 6 (ED50 0.238 mmol/kg) was the most active congener in the scPTZ model and was approximately 1.5 folds more potent than ethosuximide as reference drug Meanwhile, in the MES test, candidate drugs exhibited mild to moderate anticonvulsant efficacy, the highest of which was compound 14a, imparting 50% protection at 2.1 mmol/kg, followed by other compounds with activity ranging from 14 to 33%, as compared to diphenylhydantoin. Additionally, all candidate compounds were screened for acute neurotoxicity using the rotarod method to identify motor impairment, where almost all compounds passed the test. Further neurochemical investigation was performed to unravel the effect of the most active compound (6) on GABA level in mouse brain, where a significant elevation was evident by 4 and 1.4 folds with respect to that of the control and reference groups at p 0.05. Molecular modeling study using Discovery Studio program was performed, where compound 6 exhibited good binding interaction with γ-aminobutyric acid aminotransferase (GABA-AT) enzyme and this was consistent with the attained experimental results.
- Abd-Allah, Walaa Hamada,Anwar, Mostafa Abd-El-Mohsen,Attia, Hanan Naeim,El Moghazy, Samir M.,Osman, Essam Eldin A.
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- Synthesis and biological evaluation of novel coumarin derivatives in rhabdoviral clearance
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Diseases caused by rhabdoviruses have had a huge impact on the productive lives of the entire human population. The main problem is the lack of drugs for the treatment of this family of viruses. Infectious hematopoietic necrosis virus (IHNV), the causative agent of IHN, is a typical rhabdovirus which has caused huge losses to the salmonid industry. Therefore, in this study, IHNV was studied as a model to evaluate the antiviral activity of 35 novel coumarin derivatives. Coumarin A9 was specifically selected for further validation studies upon comparing the half maximum inhibitory concentration (IC50) of four screened candidate derivatives in epithelioma papulosum cyprinid (EPC) cells, as it exhibited an IC50 value of 2.96 μM against IHNV. The data revealed that A9 treatment significantly suppressed the virus-induced cytopathic effect (CPE) in EPC cells. In addition, A9 showed IC50 values of 1.68 and 2.12 μM for two other rhabdoviruses, spring viremia of carp virus and micropterus salmoides rhabdovirus, respectively. Furthermore, our results suggest that A9 exerts antiviral activity, but not by destroying the virus particles and interfering with the adsorption of IHNV. Moreover, we found that A9 had an inhibitory effect on IHNV-induced apoptosis in EPC cells, as reflected by the protection against cell swelling, formation of apoptotic bodies, and loss of cell morphology and nuclear division. There was a 19.05 % reduction in the number of apoptotic cells in the A9 treatment group compared with that in the IHNV group. In addition, enzyme activity assays proved that A9 suppressed the expression of caspase 3, 8 and 9. These results suggested that A9 inhibit viral replication, to some extent, by blocking IHNV-induced apoptosis. In an in vivo study, A9 exhibited an anti-rhabdovirus effect in virus-infected fish by substantially enhancing the survival rate. Consistent with the above results, A9 repressed IHNV gene expression in virus-sensitive tissues (brain, kidney and spleen) in the early stages of virus infection. Importantly, the data showed that horizontal transmission of IHNV was reduced by A9 in a static cohabitation challenge model, especially in fish that underwent bath treatment, suggesting that A9 might be a suitable therapeutic agent for IHNV in aquaculture. Therefore, coumarin derivatives can be developed as antiviral agents against rhabdoviruses.
- Chen, Jiong,Hu, Yang,Liu, Lei,Qiu, Tianxiu,Shan, Lipeng
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supporting information
(2021/08/10)
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- Antagonistic activity of hydroxycoumarin-based antioxidants as possible singlet oxygen precursor photosensitizers
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Coumarins are phenolic-type compounds with efficient antioxidant activity due to their ability to scavenge reactive oxygen species. Nevertheless, their ability to behave as photosensitizers capable of generating reactive oxygen species, such as singlet oxygen, has been less studied. In this work, the photosensitizing ability of seven hydroxycoumarins was evaluated through the photooxidation of ergosterol by quantifying the conversion of ergosterol into ergosterol peroxide. In our experimental conditions, we found that almost every tested antioxidant coumarin promotes the peroxidation of ergosterol. The results suggest that the hydroxycoumarins exhibit potential photosensitizing activity by promoting singlet oxygen generation by a Type II photochemical mechanism. Density functional theory (DFT) calculations were also performed to obtain further insight into the chemical reactivity of tested compounds; the observed tendency in the group of antioxidant coumarins to promote the reaction was their hardness due to the principle of maximum hardness. To evaluate our conclusion, we performed the reaction using a highly polarizable coumarin as a photosensitizer, which resulted in an increased photosensitizing capacity supported with DFT calculations, which reinforces our analysis. Finally, we found that hydroxycoumarins can be potentially pro-oxidants since some of them can act as photosensitizers and generate singlet oxygen in the presence of UV–Vis light, a characteristic that must be considered when these compounds are used as antioxidants.
- Guerrero, Tomás,Vázquez-Ortega, Fernanda,Lagunes, Irene,Ortiz-Blanco, Erik,Sosa-Ortiz, Gabriela,Tovar-Miranda, Ricardo,Medina, Manuel E.,Trigos, ángel
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- General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation in Vivo
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Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.
- Sun, Tao,Lv, Tian,Wu, Jianbing,Zhu, Mingchao,Fei, Yue,Zhu, Jie,Zhang, Yihua,Huang, Zhangjian
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p. 13899 - 13912
(2020/12/02)
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- Synthesis of 6- and 7-alkoxy-4-methylcoumarins from corresponding hydroxy coumarins and their conversion into 6- and 7-alkoxy-4-formylcoumarin derivatives
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Hydroxy derivatives of 4-methyl-2H-chromen-2-one were prepared from hydroquinone and resorcinol through their reaction with ethyl acetoacetate. These hydroxy coumarins were then converted into corresponding alkoxy derivatives by reaction with alkyl halides. The yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were 55?95%. Oxidation of these compounds by selenium dioxide under conventional and microwave-assisted heating conditions produced corresponding 4-formyl compounds 5b–h and 6b–h with yields of 40?67% and 90?93%, respectively. Several 6- and 7-alkoxy-4-methylcoumarins 3a–i, 4a–i and nearly all 6- and 7-alkoxy-4-formylcoumarins 5b–h, 6b–h are novel compounds.
- Ngoc Toan, Vu,Dinh Thanh, Nguyen
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supporting information
p. 3603 - 3615
(2020/08/21)
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- Synthesis and anti-proliferative activity of novel oxepin-annulated coumarins
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A series of fused dihydrooxepino[h]- and dihydrooxepino[g]coumarins (7 and 8) were synthesized through allylation, Claisen rearrangement, allylation and ring-closing metathesis (RCM), respectively. All the synthesized compounds were characterized by appropriate spectral analysis. The anti-proliferative activities of compound 5a-c, 6a, 6c, 7a-c and 8a-c were evaluated against human colon cancer (Caco-2), liver cancer (HepG2) and breast cancer (SKBR-3) cell lines using tamoxifen (TAM) as the positive control. Compound 7b showed significant anti-proliferative activity against resistant Caco-2 and SKBR-3 cell lines on comparison with all other coumarin derivatives. Interestingly, compound 8b was more potent than TAM against sensitive HepG2 cell line.
- Prateeptongkum, Saisuree,Mahavorasirikul, Wiratchanee,Duangdee, Nongnaphat
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- Synthesis of new coumarin tethered isoxazolines as potential anticancer agents
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A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2 and 4.5 μM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future.
- Lingaraju, Gejjalagere S.,Balaji, Kyathegowdanadoddi S.,Jayarama, Shankar,Anil, Seegehalli M.,Kiran, Kuppalli R.,Sadashiva, Maralinganadoddi P.
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supporting information
p. 3606 - 3612
(2018/11/06)
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- Azo Dyes: New Palladium- and Copper-Catalysed Coupling Reactions on an Old Template
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The elaboration of azo dyes using a variety of transition-metal-catalysed reactions (Stille, Heck, Ullmann, and Suzuki couplings) is reported. This methodology has been applied to the synthesis of functionalised coumarin azo dye conjugates, substrates which may find potential application in the development of new sensors.
- Rasheed, Omer K.,Quayle, Peter
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p. 2608 - 2616
(2018/05/25)
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- Design and synthesis of antimicrobial, anticoagulant, and anticholinesterase hybrid molecules from 4-methylumbelliferone
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We designed and synthesized new series of diverse triazoles, isoxazoles, isoxazolines, and aziridines linked 4-methylumbelliferone 1 using intermolecular 1,3-dipolar cycloaddition reactions. Structures of these compounds were established on the basis of 1H NMR, 13C NMR, and ESI-HRMS. All prepared compounds were evaluated for their antimicrobial, anticoagulant, and anticholinesterase activities. Interestingly, among the tested molecules, some of the analogs displayed better activities than the parent 4-methylumbelliferone 1 such as 6a and 6d for their antifungal properties. Moreover, compounds 4, 5, 6, and 7 showed the importance of the added fragments to 4-methylumbelliferone 1 via the linker methylene to have good activity.
- Zayane, Marwa,Rahmouni, Ameur,Daami-Remadi, Mejda,Ben Mansour, Mohamed,Romdhane, Anis,Ben Jannet, Hichem
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p. 1566 - 1575
(2016/10/09)
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- 4-Methylcoumarins with cytotoxic activity against T24 and RT4 human bladder cancer cell lines
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Bladder cancer is one of the most prevalent malignancies of the genitourinary tract, and approximately 25% of patients develop superficial cancers with invasive and metastatic pathology. Coumarins and their derivatives have antiproliferative activity and
- Vianna,Ruschel,Dietrich,Figueiró,Morrone,Canto,Corvello,Velho,Crestani,Teixeira,Von Poser,Battastini,Eifler-Lima
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p. 905 - 911
(2015/05/27)
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- A new route to pyranocoumarins and their benzannulated derivatives
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A new protocol based on sequential applications of three atom-economic processes viz. Claisen rearrangement, olefin isomerisation, and ring-closing diene metathesis has been developed to access a range of linear and angularly fused pyranocoumarin derivatives. Incorporation of enyne (in place of diene) metathesis and Diels-Alder reaction in the sequence has allowed the corresponding benzannulated derivatives to be prepared in good yields.
- Chattopadhyay, Shital K.,Mondal, Poulomi,Ghosh, Debalina
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p. 3331 - 3340
(2015/02/18)
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- Synthesis, spectral characterization and α-chymotrypsin activity of 7-O-substituted derivatives of 7-hydroxy-4-methyl-1-benzopyran-2-one
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In this work, a series of O-alkyl/arenyl/acyl substituted derivatives of 7-hydorxy-4-methyl-1-benzenpyran-2-one (3a-l) was synthesized. The parent compound 7-hydroxy-4-methyl-1-benzenpyran-2-one (1) was geared up by the coupling of resorcinol (a) with ethylacetoacetate (b) in the presence of conc. sulphuric acid. Further, O-substituted derivatives of parent compound were prepared by treating with different electrophiles (2a-l) using sodium hydride as base and DMF as a solvent. The structure of these synthesized compounds were characterized by IR, EI-MS and 1H NMR. These derivatives were also screened against α-chymotrypsin enzyme to check their enzyme inhibition activity. All the compounds displayed a-chymotrypsin activity to varying degree.
- Aziz-Ur-Rehman,Ilyas, Tehseen,Abbasi, Muhammad Athar,Nafeesa, Khadija,Khaliq, Shaista,Rubab, Kaniz,Hussain, Ghulam,Khurshid, Shazia,Ahmad, Irshad
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p. 326 - 330
(2014/06/09)
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- Synthesis and anthelmintic activity of osthol analogs against Dactylogyrus intermedius in goldfish
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In an attempt to develop novel anthelmintic agents, our previously isolated osthol was used as lead structures for further optimization. In our research, a series of coumarin analogs, prepared from 7-hydroxy coumarin or 7-hydroxy-4-methyl coumarin, have been evaluated for their anthelmintic activities. In all of the compounds, 6 and 7 were first synthesized, and their structures were identified based on NMR and MS values. Among the candidates, 8-allyl-7-allyloxycoumarin showed better anthelmintic activity than other compounds against Dactylogyrus infestation with EC50 value of 1.81 mg/L. The quantitative structure-activity relationship (QSAR) of 16 osthol analogs with anthelmintic activity expressed as pEC50 and toxicity to goldfish expressed pLC50, such results can offer useful theoretical references for future experimental works.
- Liu, Guang-Lu,Hao, Bing,Liu, Shao-Peng,Wang, Gao-Xue
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experimental part
p. 582 - 590
(2012/09/11)
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- Establishing a flow process to coumarin-8-carbaldehydes as important synthetic scaffolds
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Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe here a high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up, giving access to multigram quantities of the aldehyde product. Aldehyde on tap: Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8- carbaldehydes are lacking. A high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up is described, giving access to multigram quantities of aldehyde product (see scheme). Copyright
- Zak, Jaroslav,Ron, David,Riva, Elena,Harding, Heather P.,Cross, Benedict C. S.,Baxendale, Ian R.
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supporting information; experimental part
p. 9901 - 9910
(2012/09/07)
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- Synthesis and biological evaluation of fused oxepinocoumarins as free radicals scavengers
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Some fused dihydrooxepino[f]-, [g]-, and [h]coumarins were obtained from the ring-closing metathesis of the corresponding o-allyl-allyloxycoumarins under the treatment with the first generation Grubbs' catalyst. These compounds were tested in vitro for their antioxidant activity, and they present significant scavenging activity. They were also showed to inhibit in vitro soybean lipoxygenase.
- Litinas, Konstantinos E.,Mangos, Alexandros,Nikkou, Thomas E.,Hadjipavlou-Litina, Dimitra J.
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experimental part
p. 805 - 812
(2012/04/04)
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- DEVELOPMENT OF FLUOROGENIC SUBSTRATES FOR MONOAMINE OXIDASES (MAO-A AND MAO-B)
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The present invention relates to compounds useful for detecting the activity of monoamine oxidases, compounds useful for competitively inhibiting monoamine oxidases, for determining inhibitors of monoamine oxidases and compounds useful for treating monoamine oxidase-related nervous system pathologies, as well as pharmaceutical compositions and methods of manufacture thereof.
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Page/Page column 99
(2008/06/13)
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- Enzyme activity fingerprinting with substrate cocktails
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In the postgenomic era, emphasis is shifting from protein identification to protein functional analysis. Enzyme function can be characterized by measuring activity across series of substrates, which generates an activity profile or fingerprint. Activity f
- Goddard, Jean-Philippe,Reymond, Jean-Louis
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p. 11116 - 11117
(2007/10/03)
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- Microwave and BF3 promoted rearrangement of allyloxycoumarins to allylcoumarins and dihydrofurocoumarins
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Allyl, crotyl, methallyl and cinamyl ethers of 4-hydroxy-, 7-hydroxy-, and 4-methyl-7-hydroxycoumarins have been efficiently synthesized and rearranged to substituted allylcoumarins under microwave irradiation. Irradiation of allylcoumarins in the presence of BF3/ether directly produced substituted dihydrofurocoumarins in good yields.
- Saidi, Mohammad R,Rajabi, Fatemeh
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p. 1805 - 1812
(2007/10/03)
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- DDQ Oxidation of 6- or 8-Allyl-7-hydroxycoumarins. A New Synthesis of Benzodipyrandiones and Furobenzopyranones
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A novel synthesis of 2H,8H-benzodipyran-2,8-diones, 2H,8H-benzodipyran-2,8-diones, 2H-furobenzopyran-2-ones, and 7H-furobenzopyran-7-ones was achieved by developing 2-pyrone and furan ring over coumarin. 6- or 8-Allyl-7-hydroxycoumarins on oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) afforded benzodipyrandiones and furobenzopyranones.The structures of the compounds now synthesized were established by analytical, spectral, and comparison with authentic samples prepared by the known procedures.
- Prashant, Avula,Krupadanam, Gazula Levi David,Srimannarayana, Gutely
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p. 1191 - 1193
(2007/10/02)
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- Curable fluorescent organopolysiloxane compositions
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Fluorescent organopolysiloxane compounds which bear two or more reactive silicon-bonded sites are useful as durable markers in curable silicone compositions. Having more than one reactive site the compounds participate in the curing reaction of the curable composition and thus do not adversely affect its curing behavior. The resulting fluorescent curable compositions are particularly useful in the preparation of adhesive-release coatings.
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- Synthesis of some photosensitizing methylangelicins, as monofunctional reagents for DNA
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angelicins methylated angelicans were synthesized for obtaining monofunctional reagents for DNA; these compounds may present some interest with regard to the development of useful drugs in photochemotheapy. The new derivatives photobind covalently to DNA, however, they are unable to produce inter-strand, cross-linkages in the macromolecule. Thephotobiological activity was tested on phage T2 and was higher for the methylated derivatives than for angelicin.
- Guiotto,Rodighiero,Pastorini,et al.
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p. 489 - 494
(2007/10/02)
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- 8-Aminoalkyl-4-alkylisopsoralens
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The invention relates to 8-aminoalkyl-4-alkylisopsoralens, especially 8-aminomethyl-4-methylisopsoralen, having enhanced photosensitizing activity, especially oral and topical activity, pharmaceutical compositions thereof, and method of effecting photosensitization therewith.
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