- Azaaurones as Potent Antimycobacterial Agents Active against MDR- and XDR-TB
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Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N-acetylazaaurones, against Mycobacterium tuberculosis. Aurones were found to be inactive at 20 μm, whereas azaaurones and N-acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC99 values ranging from 0.4 to 2.0 μm. In addition, several N-acetylazaaurones were found to be active against multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical M. tuberculosis isolates. The antimycobacterial mechanism of action of these compounds remains to be determined; however, a preliminary mechanistic study confirmed that they do not inhibit the mycobacterial cytochrome bc1 complex. Additionally, microsomal metabolic stability and metabolite identification studies revealed that N-acetylazaaurones are deacetylated to their azaaurone counterparts. Overall, these results demonstrate that azaaurones and their N-acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.
- Campani?o, André,Carrasco, Marta P.,Njoroge, Mathew,Seldon, Ronnett,Chibale, Kelly,Perdig?o, Jo?o,Portugal, Isabel,Warner, Digby F.,Moreira, Rui,Lopes, Francisca
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p. 1537 - 1546
(2019/08/02)
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- Transition-metal-free synthesis of polysubstituted pyrrole derivatives via cyclization of methyl isocyanoacetate with aurone analogues
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Presented herein is an unprecedented transition-metal-free cyclization of methyl isocyanoacetate with aurone analogues catalyzed by NaOH. Various 2,3,4-trisubstituted pyrroles were obtained in excellent yields (up to 99%). The high efficiency of this synthetic procedure, coupled with the operational simplicity and atom economy, makes it an attractive method for the synthesis of polysubstituted pyrroles.
- Wang, Zhi-Peng,He, Yun,Shao, Pan-Lin
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supporting information
p. 5422 - 5426
(2018/08/12)
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- Catalytic Asymmetric [3 + 2] Cycloaddition Reaction between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis
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The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with isocyanoacetates was developed via chiral Ag-complex catalysis. A variety of optically enriched spiro-1-pyrrolines were obtained in excellent yields, diastero- and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient, and atom-economical method for spiro-1-pyrrolines synthesis.
- Wang, Zhi-Peng,Xiang, Sichuan,Shao, Pan-Lin,He, Yun
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p. 10995 - 11007
(2018/07/21)
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- Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents
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Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphos
- Priyadarshani, Garima,Nayak, Anmada,Amrutkar, Suyog M.,Das, Sarita,Guchhait, Sankar K.,Kundu, Chanakya N.,Banerjee, Uttam C.
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p. 1056 - 1061
(2016/12/18)
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- Copper-catalyzed intramolecular tandem reaction of (2-halogenphenyl)(3- phenyloxiran-2-yl)methanones: Synthesis of (Z)-aurones
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A convenient and efficient method for the copper-catalyzed synthesis of (Z)-aurones via intramolecular tandem reaction of (2-halogenphenyl)(3- phenyloxiran-2-yl)methanones is reported. Moreover, a plausible mechanism for the formation of (Z)-aurones is proposed. This is the first report on the synthesis of (Z)-aurones through copper-catalyzed Ullmann coupling reaction employing epoxides as substrates.
- Weng, Yiyi,Chen, Qixu,Su, Weike
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p. 4218 - 4224
(2014/05/20)
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- Probing the aurone scaffold against Plasmodium falciparum: Design, synthesis and antimalarial activity
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A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC 50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
- Carrasco, Marta P.,Newton, Ana S.,Gon?alves, Lídia,Góis, Ana,Machado, Marta,Gut, Jiri,Nogueira, Fátima,H?nscheid, Thomas,Guedes, Rita C.,Dos Santos, Daniel J.V.A.,Rosenthal, Philip J.,Moreira, Rui
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p. 523 - 534
(2014/05/20)
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- Synthesis of aurones under neutral conditions using a deep eutectic solvent
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Aurones are an interesting, but little studied member of the flavanoid family of natural products. Of the various methods available for their synthesis, the simplest involves the condensation of a coumaranone with an aldehyde. This reaction can be perform
- Hawkins, Ian,Handy, Scott T.
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p. 9200 - 9204
(2013/10/01)
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- Ethylenediamine diacetate (EDDA) mediated synthesis of aurones under ultrasound: Their evaluation as inhibitors of SIRT1
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An improved synthesis of functionalized aurones has been accomplished via the reaction of benzofuran-3(2H)-one with a range of benzaldehydes in the presence of a mild base EDDA under ultrasound. A number of aurones were synthesized (within 5-30 min) and the molecular structure of a representative compound determined by single crystal X-ray diffraction study confirmed Z-geometry of the C-C double bond present within the molecule. Some of the compounds synthesized have shown SIRT1 inhibiting as well as anti proliferative properties against two cancer cell lines in vitro. Compound 3a [(Z)-2-(5-bromo-2-hydroxybenzylidene) benzofuran-3(2H)-one] was identified as a potent inhibitor of SIRT1 (IC50 = 1 μM) which showed a dose dependent increase in the acetylation of p53 resulting in induction of apoptosis.
- Manjulatha, Khanapur,Srinivas,Mulakayala, Naveen,Rambabu,Prabhakar,Arunasree, Kalle M.,Alvala, Mallika,Basaveswara Rao,Pal, Manojit
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p. 6160 - 6165
(2012/10/30)
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- Aurones: Small molecule visible range fluorescent probes suitable for biomacromolecules
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Aurones, derivatives of 2-benylidenebenzofuran-3 (2H)-one, are natural products that serve as plant pigments. There have been reports that some of these substances fluoresce, but little information about their optical properties is in the literature. In this report, series of aurone derivatives were synthesized as possible fluorescent probes that can be excited by visible light. We found that an amine substituent shifted the lowest energy absorption band from the near-UV to the visible region of the electromagnetic spectrum. Four amine-substituted aurone derivatives were synthesized to explore the effect of this substituent on the absorption and emission properties of the aurone chromophore. The emission maxima and intensities of the molecules are strongly dependent on the nature of the substituent and the solvent polarity. Overall, the emission intensity increases and the maximum wavelength decreases in less polar solvents; thus, the aurones may be useful probes for hydrophobic sites on biological molecules. A limited investigation with model protein, nucleic acid and fixed cells supports this idea. It is known that the sulfur analog of aurone can undergo photoinduced E/Z isomerization. This possibility was investigated for one of the aminoaurones, which was observed to reversible photoisomerize. The two isomers have similar absorption spectra, but the emission properties are distinct. We conclude that appropriately substituted aurones are potentially useful as biological probes and photoswitches. Springer Science+Business Media, LLC 2011.
- Shanker, Natasha,Dilek, Ozlem,Mukherjee, Kamalika,McGee, Dennis W.,Bane, Susan L.
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p. 2173 - 2184
(2012/06/15)
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- FLAVONOIDS, XXXVII. RING CONTRACTION AND RING ENLARGEMENT REACTIONS WITH TRIMETHYLSILYL AZIDE IN THE FIELD OF FLAVONOIDS
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The reaction of flavanone with trimethylsilyl azide (TMSA) in trifluoroacetic acid (TFA) afforded by ring expansion, 2,3-dihydro-2-phenyl-1,4-benzoxazepin-5(4H)-one or 2,3-dihydro-2-phenyl-4H-tetrazolo-1,4-benzoxazepine.The same products could be isolated using sodium azide in TFA.An unknown intermediate of the Schmidt reaction was also isolated.Treatment of 2'-hydroxychalcone with TMSA or sodium azide in TFA resulted in isoflavone and trans-3-aminoflavanone.The reaction of 4-substituted 2'-hydroxychalcones with TMSA in dimethylformamide gave, with ring contraction, aurones and flavones.
- Litkei, Gy.,Patonay, T.
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- FLAVONOIDS, XXXVI REACTION OF 3-ALKYL- OR -ARYLSULFONYLOXYFLAVANONES WITH AMINES. SYNTHESIS OF 3-DIALKYLAMINOFLAVANONES
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Reactions of 3-alkyl- or -arylsulfonyloxyflavanones (1a-h) with primary and tertiary amines gave mixtures of the corresponding flavones (2a-d) and aurones (3a-d), while with secondary amines, in addition to 2 and 3, 3-dialkylaminoflavanones (6-9) were also obtained.The factors which determine the ratio of products are discussed.Treatment of the 3-dialkylaminoflavones 6a and 7 with DDQ gave 3-dialkylaminoflavanones (10, 11); treatment with alkali in methanol afforded 2-dialkylamino-2-benzylcoumaran-3-ones (12, 13).
- Patonay, T.,Litkei, Gy.,Bognar, R.
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p. 135 - 146
(2007/10/02)
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