- Pd/C-mediated synthesis of (Z)-3-alkylidenephthalides of potential pharmacological interest
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The coupling of o-bromobenzoic acid with terminal alkynes using 10% Pd/C-Et3N-CuI-PPh3 as a catalyst system leads to the synthesis of (Z)-3-alkylidenephthalides as the major product along with the traces of isocoumarin when the reaction was performed in 1,4-dioxane. The methodology afforded a range of compounds including (Z)-3-(4-(methylsulfonyl) benzylidene)isobenzofuran-1(3H)-one of potential pharmacological interest.
- Rambabu,Kumar, G. Pavan,Kumar, Barange Deepak,Kapavarapu, Ravikumar,Rao, M.V. Basaveswara,Pal, Manojit
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- Imidazo[2,1-a]isoindole scaffold as an uncharted structure active on Leishmania donovani
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The human protozoan parasites Leishmania donovani and L. infantum are the causative agents of visceral leishmaniasis, as such, responsible for approximately 30,000 deaths annually. The available chemotherapeutic treatments are reduced to a few drugs whose effectiveness is limited by rising drug resistance/therapeutic failure, and noxious side-effects. Therefore, new therapeutic hits are needed. Compounds displaying the imidazo[2,1-a]isoindole skeleton have shown antichagasic, anti-HIV, antimalarial and anorectic activities. Here, we report the leishmanicidal activity of thirty one imidazo[2,1-a]isoindol-5-ol derivatives on promastigotes and intracellular amastigotes of L. donovani. Eight out of thirty one assayed compounds showed EC50 values ranging between 1 and 2 μM with selectivity indexes from 29 to 69 on infected THP-1 cells. Six compounds were selected for further elucidation of their leishmanicidal mechanism. In this regard, compound 29, the imidazoisoindolol with the highest activity on intracellular amastigotes, induced an early decrease of intracellular ATP levels, as well as mitochondrial depolarization, together with a partial plasma membrane destructuration, as assessed by transmission electron microscopy. Consequently, the inhibition of the energy metabolism of Leishmania plays an important role in the leishmanicidal mechanism of this compound, even when other additional targets cannot be ruled out. In all, the results supported the inclusion of the imidazoisoindole scaffold for the development of new leishmanicidal drugs.
- Arsène, Sobinson,Gómez-Pérez, Verónica,Escarcena, Ricardo,Abengózar, María ángeles,García-Hernández, Raquel,Nácher-Vázquez, Montserrat,San Feliciano, Arturo,Gamarro, Francisco,Rivas, Luis,Olmo, Esther del
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- Regio- and Stereoselective Synthesis of (Z)-3-Ylidenephthalides via H3PMo12O40-Catalyzed Cyclization of 2-Acylbenzoic Acids with Benzylic Alcohols
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We report an exclusively tandem C—O and C—C bond forming beyond the esterification and cyclization reaction of 2-acylbenzoic acids with alcohols to regio- and stereoselective synthesis of the (Z)-3-ylidenephthalides. The reaction uses the nontoxic, inexpensive H3PMo12O40 as catalyst and produces water as the sole by-product, making the reaction environmentally benign and sustainable. Moreover, this reaction features an eco-friendly reaction condition, facile scalability, and easy derivatization of the products to drugs and bioactive compounds. The mechanism studies and density functional theory calculations reveal that the appropriate acid catalyst is the key to the selectivity of this transformation.
- Yang, Guoping,Li, Ke,Lin, Xiaoling,Li, Yijin,Cui, Chengxing,Li, Shixiong,Cheng, Yuanyuan,Liu, Yufeng
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p. 3017 - 3022
(2021/09/13)
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- Design, synthesis and biological evaluation of substituted flavones and aurones as potential anti-influenza agents
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We designed a series of substituted flavones and aurones as non-competitive H1N1 neuraminidase (NA) inhibitors and anti-influenza agents. The molecular docking studies showed that the designed flavones and aurones occupied 150-cavity and 430-cavity of H1N1-NA. We then synthesized these compounds and evaluated these for cytotoxicity, reduction in H1N1 virus yield, H1N1-NA inhibition and kinetics of inhibition. The virus yield reduction assay and H1N1-NA inhibition assay demonstrated that the compound 1f (4-methoxyflavone) had the lowest EC50 of 9.36 nM and IC50 of 8.74 μM respectively. Moreover, kinetic studies illustrated that compounds 1f and 2f had non-competitive inhibition mechanism.
- Chintakrindi, Anand S.,Gohil, Devanshi J.,Chowdhary, Abhay S.,Kanyalkar, Meena A.
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supporting information
(2019/11/29)
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- Ag2O nanoparticle-catalyzed substrate-controlled regioselectivities: direct access to 3-ylidenephthalides and isocoumarins
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Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides 11-16 and isocoumarins 17-20via sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively. This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions, operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition experiments and gram-scale synthesis further highlight the importance and versatility of the methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially being controlled by the substituent(s) present on the acetylenic phenyl ring.
- Chaudhary, Sandeep,Shyamlal, Bharti Rajesh K.,Yadav, Lalit,Tiwari, Mohit K.,Kumar, Krishan
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p. 23152 - 23162
(2018/07/10)
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- Phenylidene phenyl peptide compounds and medicinal composition and application thereof
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The invention provides phenylidene phenyl peptide compounds, a medicinal composition using the phenylidene phenyl peptide compounds as active components, and application thereof as monoamine oxidase B(MAO-B) inhibitors and application thereof to preparation of medicines for treating Parkinson's disease (PD). Monoamine oxidase B (MAO-B) has been proved to be closely related to the pathogenesis ofthe Parkinson's disease (PD) and is a classic target for research and development of the medicines for treating the Parkinson's disease (PD). The invention provides application of the phenylidene phenyl peptide compounds to preparation of the monoamine oxidase B (MAO-B) inhibitors. In-vitro kinase activity experiments prove that the phenylidene phenyl peptide compounds have a significant monoamineoxidase B (MAO-B) inhibiting effect.
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Paragraph 0049-0051; 0062-0065
(2018/11/22)
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- Transition-metal-free synthesis of (Z)-3-ylidenephthalides from 2-acyl-benzoic acids
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We report a highly efficient method for the synthesis of (Z)-3-ylidenephthalides via intramolecular cyclization of readily available 2-acyl-benzoic acids mediated by TSTU at room temperature. Using this method, diversely substituted (Z)-3-ylidenephthalides have been generated in good to excellent yields. The application of the method is highlighted by gram-scale preparation of the antiplatelet drug n-butylphthalide.
- He, Xinhua,Xue, Fengtian
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p. 1956 - 1958
(2014/03/21)
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- New method for the synthesis of lactones via nickel-catalyzed isocyanides insertion
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A novel nickel catalyst for the reaction of tert-butyl isocyanide insertion was discovered. In this approach, 1,2-bis(diphenylphosphino)ethane (L3) serves as an efficient ligand, thereby allowing the preparation of lactones from (o-bromophenyl)phenylethanone derivatives. It is noteworthy that this is the first example of nickel acting as a metal catalyst in the reactions of tert-butyl isocyanide insertion. The significance of this methodology may draw many chemists attention in the field of isocyanide-incorporating reactions. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]
- Fei, Xiang-Dong,Tang, Ting,Ge, Zhi-Yuan,Zhu, Yong-Ming
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p. 3262 - 3271
(2013/10/01)
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- 3-Ylidenephthalides as a new class of transient receptor potential channel TRPA1 and TRPM8 modulators
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Following the recent identification of the naturally occurring 3-ylidene-4,5-dihydrophthalide ligustilide and its oxidation product dehydroligustilide as novel TRPA1 modulators, a series of seventeen 3-ylidenephthalides was synthesized and tested on TRPA1 and TRPM8 channels. Most of these compounds acted as strong modulators of the two channel types with EC50 and/or IC50 values distinctly lower than those of the reference compounds.
- Ortar, Giorgio,Schiano Moriello, Aniello,Morera, Enrico,Nalli, Marianna,Di Marzo, Vincenzo,De Petrocellis, Luciano
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p. 5614 - 5618
(2013/10/01)
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- Synthesis, bioevaluation and structural study of substituted phthalazin-1(2H)-ones acting as antifungal agents
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Twenty-five polysubstituted phthalazinone derivatives were synthesized and tested for their antifungal activity against a panel of pathogenic and clinically important yeasts and filamentous fungi. Among them, the compound 4-(4-chlorobenzyl)-2- methylphthalazin-1(2H)-one (5) exhibited a remarkable antifungal activity against standardised strains of dermatophytes and Cryptococcus neoformans, as well as against some clinical isolates. A physicochemical study performed on compound 5 revealed its conformational and electronic characteristics, providing us with useful data for the future design of novel related antifungal analogues.
- Derita, Marcos,Del Olmo, Esther,Barboza, Bianca,Garcia-Cadenas, Ana Esther,Lopez-Perez, Jose Luis,Andujar, Sebastian,Enriz, Daniel,Zacchino, Susana,Feliciano, Arturo San
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p. 3479 - 3501
(2013/05/09)
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- Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds
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The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC50 values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models.
- Olmo, Esther Del,Barboza, Bianca,Chiaradia, Louise D.,Moreno, Alicia,Carrero-Lérida, Juana,González-Pacanowska, Dolores,Mu?oz, Victoria,López-Pérez, José L.,Giménez, Alberto,Benito, Agustín,Martínez, Antonio R.,Ruiz-Pérez, Luis M.,San Feliciano, Arturo
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experimental part
p. 5379 - 5386
(2011/12/14)
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- Anti-HIV activity of stilbene-related heterocyclic compounds
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Viral transcription has not been routinely targeted in the development of new antiviral drugs. This crucial step of the viral cycle depends on the concerted action of cellular and viral proteins such as NF-κB and Tat. In the present study, stilbene-related heterocyclic compounds including benzalphthalide, phthalazinone, imidazoindole and pyrimidoisoindole derivatives are tested for their anti-HIV activity. Original assays based on recombinant viruses were used to evaluate HIV replication inhibition and stably transfected cell lines were used to evaluate inhibition of Tat and NF-κB proteins. Some of the stilbene-related heterocyclic compounds analysed displayed anti-HIV activity through interference with NF-κB and Tat function. Moreover, compounds inhibiting both targets displayed a stronger activity on viral replication.
- Bedoya, Luis M.,del Olmo, Esther,Sancho, Rocio,Barboza, Bianca,Beltran, Manuela,Garcia-Cadenas, Ana E.,Sanchez-Palomino, Sonsoles,Lopez-Perez, Jose L.,Munoz, Eduardo,Feliciano, Arturo San,Alcami, Jose
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p. 4075 - 4079
(2007/10/03)
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- Vasorelaxant activity of phthalazinones and related compounds
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Several series of dihydrostilbenamide, imidazo[2,1-a]isoindole, pyrimido[2,1-a]isoindole and phthalazinone derivatives were obtained and their vasorelaxant activity was measured on isolated rat aorta rings pre-contracted with phenylephrine (10-5 M). Some phthalazinones attained, practically, the total relaxation of the organ at micromolar concentrations. For the most potent compound 9h (EC50 = 0.43 μM) the affinities for α1A, α1B and α1D adrenergic sub-receptors were determined.
- Olmo, Esther del,Barboza, Bianca,Ybarra, Ma Ines,Lopez-Perez, Jose Luis,Carron, Rosalia,Sevilla, Ma Angeles,Boselli, Cinthia,Feliciano, Arturo San
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p. 2786 - 2790
(2007/10/03)
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- Anxiolytic effects of benzalphthalides
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Anxiolytic effects induced by benzalphthalides on mice have been evaluated. The evaluation was based on the spent time and the number of entries of animals into the open arms in the elevated plus maze test. Single administration of benzalphthalides 1 and 11 induced significant increments in both parameters, thus revealing their potentiality as new leads for the development of non-benzodiazepinic and non-nitrogenated antianxiety agents.
- Zamilpa, Alejandro,Herrera-Ruiz, Maribel,Del Olmo, Esther,Lopez-Perez, Jose L.,Tortoriello, Jaime,San Feliciano, Arturo
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p. 3483 - 3486
(2007/10/03)
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- Synthesis of 3-arylisocoumarins, including thunberginols A and B, unsymmetrical 3,4-disubstituted isocoumarins, and 3-ylidenephthalides via iodolactonization of methyl 2-ynylbenzoates or the corresponding carboxylic acids
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3-Aryl-4-iodoisocoumarins, which were readily and efficiently prepared by regioselective iodolactonization of methyl 2-ynylbenzoates or the corresponding carboxylic acids, were used as precursors either to 3-arylisocoumarins, including naturally-occurring
- Rossi, Renzo,Carpita, Adriano,Bellina, Fabio,Stabile, Paolo,Mannina, Luisa
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p. 2067 - 2081
(2007/10/03)
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- Leishmanicidal activity of some stilbenoids and related heterocyclic compounds
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We have evaluated the leishmanicidal activity of some natural and semisynthetic dihydrostilbenoids and several compounds of other series of dihydrostilbamides, isoindoles, phthalazinones, imidazoisoindoles and pyrimidoisoindoles. The evaluation was performed in vitro, on cultures of cutaneous, mucocutaneous and visceral strains of Leishmania spp. The most potent and selective compounds of these series were the dihydrostilbene piperidides.
- Del Olmo, Esther,Armas, Marlon Garcia,Lopez-Perez, Jose Luis,Muoz, Victoria,Deharo, Eric,San Feliciano, Arturo
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p. 2123 - 2126
(2007/10/03)
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- THE CHEMISTRY OF PHTALIDE-3-CARBOXYLIC ACID - I DECARBOXYLATION ON THE PRESENCE OF THE ALDEHYDES
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The decarboxylation of phthalide-3-carboxylic acid (3-oxo-1,3-dihydroisobenzofuran-1-carboxylic acid) has been studied in the melt, in dimethylsulfoxide, and in the presence of aromatic aldehydes.The latter are efficiently trapped to produce mixtures of 3-arylidene-phthalides and 3-(arylhydroxymethyl)phthalides.Kinetic and other evidence supports the proposal that this reaction occurs in a tight cyclic transition state.
- Prager, Rolf H.,Schiesser, Carl H.
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p. 1517 - 1522
(2007/10/02)
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- Benzalphthalides and broad spectrum sun screens
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Compositions containing a benzalphthalide, i.e. benzalphthalide or a substituted benzalphthalide, are very effective broad spectrum sun screens. They are prepared by reacting substituted or unsubstituted phthalic anhydride with the corresponding substituted or unsubstituted phenyl acetic acid.
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