- Design, synthesis, computational and biological evaluation of new anxiolytics
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New anxiolytics have been discovered by prediction of biological activity with computer programs pass and derek for a heterogeneous set of 5494 highly chemically diverse heterocyclic compounds (thiazoles, pyrazoles, isatins, a-fused imidazoles and others)
- Geronikaki, Athina,Babaev, Eugeni,Dearden, John,Dehaen, Wim,Filimonov, Dmitrii,Galaeva, Irina,Krajneva, Valentina,Lagunin, Alexey,MacAev, Fliur,Molodavkin, Guenadiy,Poroikov, Vladimir,Pogrebnoi, Serghei,Saloutin, Victor,Stepanchikova, Alla,Stingaci, Eugenia,Tkach, Natalia,Vlad, Liudmila,Voronina, Tatiana
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- Base-promoted expedient access to spiroisatins: Synthesis and antitubercular evaluation of 1 h -1,2,3-triazole-tethered spiroisatin-ferrocene and isatin-ferrocene conjugates
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The use of sodium hydride provides a convenient access to the synthesis of C-5-functionalized spiroisatins with the absence of the typical drawbacks associated with conventional protocols. The synthesized precursors, viz. N-alkylazido spiroisatins and their unprotected counterparts, were explored in Cu-mediated azide-alkyne cycloaddition reactions to probe the antitubercular structure-activity relationships (SAR) within the isatin-ferrocene-triazole conjugate family. The antitubercular evaluation studies of the synthesized conjugates revealed an improvement in the minimal inhibitory concentration (MIC) with the introduction of ferrocene nucleus, as evidenced by spiroisatin-ferrocene and isatin-ferrocene hybrids.
- Kumar, Kewal,Biot, Christophe,Carrere-Kremer, Severine,Kremer, Laurent,Guerardel, Yann,Roussel, Pascal,Kumar, Vipan
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- Triarylethylene-indolin-2,3-dione molecular conjugates: Design, synthesis, docking studies and anti-proliferation evaluation
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A series of 1H-1,2,3-triazole-linked ospemifene-isatin and O-methylated ospemifene-isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells. The non-cytotoxic conjugate 14e, with an optimal combination of bromo substituents at the C-5/C-7 positions of isatin, proved to be a promising hit with an IC50 value of 31.62 μM against MCF-7 and 19.23 μM against MDA-MB-231. The observed anti-proliferative activities of active conjugates were further corroborated via docking studies carried out on estrogen receptor subtypes α and β.
- Kumar, Sumit,Palma, Gabriella,Perumal, Shanen,Kaur, Mandeep,Singh-Pillay, Ashona,Raj, Raghu,Singh, Parvesh,Kumar, Vipan
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p. 42409 - 42414
(2020/01/08)
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- Design, synthesis, anti-proliferative evaluation and docking studies of 1: H -1,2,3-triazole tethered ospemifene-isatin conjugates as selective estrogen receptor modulators
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A library of 1H-1,2,3-triazole-tethered ospemifene-isatin and ospemifene-spiroisatin conjugates have been synthesized and evaluated for their anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines. The evaluation studies revealed that compound 11j was the most potent with an IC50 value of 1.56 μM against the MCF-7 cell line. Compounds 11k and 11l also displayed a similar trend, with several-fold lower effective concentrations in ER+ cells than in ER- cells. SAR studies revealed that conjugates having a bromo-substituent at the C-5 and C-7 positions of the isatin ring with ethyl/propyl as the spacer were observed to be active with the most potent compound being ～30 times more potent than Tamoxifen against the MCF-7 cell line. The evaluation results were further supported by docking studies and the stronger binding affinity of the synthesized conjugates was attributed to their greater structural bulk and greater occupation of the ERα active site.
- Kumar, Sumit,Gu, Liang,Palma, Gabriella,Kaur, Mandeep,Singh-Pillay, Ashona,Singh, Parvesh,Kumar, Vipan
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p. 3703 - 3713
(2018/03/06)
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- Strategic synthesis and in vitro antimicrobial evaluation of novel difluoromethylated 1-(1, 3-diphenyl-1H-pyrazol-4-yl)-3, 3-difluoro-1, 3-dihydro-indol-2-ones
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A strategic synthesis of 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones has been achieved by the reaction of indole-2,3-dione (isatin) and substituted bromoacetyl benzene followed by cyclization reaction and evaluated for in vitro antibacterial and antifungal activities. Direct fluorination using diethylaminosulfur trifluoride as a nucleophilic fluorinating reagent was carried out in the present paper. Undoubtedly this methodology gives a facile and straightforward pathway to construct 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones in good yields. The structure of new fluorinated 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones was characterized based on 1H, 13C, and 19F nuclear magnetic resonance spectroscopy and mass spectrometry data. Structure of target compound was confirmed by Nuclear Overhauser Effect Spectroscopy spectra. Some of the synthesized compounds showed good antimicrobial activities against bacteria and fungi.
- Chundawat, Tejpal Singh,Kumari, Poonam,Sharma, Nutan,Bhagat, Sunita
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p. 2335 - 2348
(2016/10/25)
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- Design, synthesis and preliminary biological evaluation of indoline-2,3-dione derivatives as novel HDAC inhibitors
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Histone deacetylases (HDACs) are zinc-dependent or NAD+ dependent enzymes and play a critical role in the process of tumor development. Herein a series of indoline-2,3-dione derivatives have been designed and synthesized as potential HDACs inhibitors. The preliminary biological evaluation showed that most compounds synthesized have exhibited moderate Hela cell nuclear extract inhibitory activities, among which compound 25a (IC50 = 10.13 nM) has shown the best efficacy. The anti-proliferative activities of some of these compounds were also discussed.
- Jin, Kang,Li, Shanshan,Li, Xiaoguang,Zhang, Jian,Xu, Wenfang,Li, Xuechen
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p. 4728 - 4736
(2015/08/03)
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- Synthesis of 1,2,3-benzotriazin-4-one derivatives containing spirocyclic indoline-2-one moieties and their nematicidal evaluation
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To discover new chemotypes of nematicides with proper toxicological profiles, a series of novel 1,2,3-benzotriazin-4-one derivatives were synthesized and further bioevaluated. The bioassay results showed that most of the synthesized compounds were endowed with moderate to good control efficacy against Meloidogyne incognita at 10.0 mg/L in vivo. Among them, compounds 6k and 6p displayed 100% inhibitory activities at this concentration, which implied that they could be used as lead compounds for promising nematicides.
- Wang, Gao-Lei,Chen, Xi,Chang, Ya-Ning,Du, Dan,Li, Zhong,Xu, Xiao-Yong
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p. 1502 - 1506
(2015/12/23)
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- Novel 2-oxoindoline-based hydroxamic acids: Synthesis, cytotoxicity, and inhibition of histone deacetylation
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In a continuation of a research program to discover novel small molecules targeting histone deacetylases, a series of 2′-oxospiro[1,3]dioxolane/dithiolane-2,3′-indoline-based hydroxamic acids have been designed and synthesized. These 2-oxoindoline-based hydroxamic acids displayed potent cytotoxicity against three human cancer cell lines, including SW620 (colon cancer), PC-3 (prostate cancer) and AsPC-1 (pancreatic cancer), with IC50 values as low as 0.05-0.07 μM, 74-fold lower than that of SAHA (1.64-3.70 μM). Additionally, compounds in this series exhibited good inhibition against histone-H3 and histone-H4 deacetylation, as evaluated by Western blot assay. These compounds also strongly inhibited HDAC2 with IC50 values as low as 0.03 μM. Docking studies performed using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.7 to -8.0 kcal/mol) compared to SAHA (-7.4 kcal/mol).
- Huong, Tran Thi Lan,Dung, Do Thi Mai,Dung, Phan Thi Phuong,Huong, Phung Thanh,Vu, Tran Khac,Hahn, Hyunggu,Han, Byung Woo,Kim, Jisung,Pyo, Minji,Han, Sang-Bae,Nam, Nguyen-Hai
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supporting information
p. 6425 - 6429
(2015/11/16)
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- Enantioselective N-alkylation of isatins and synthesis of chiral N-alkylated indoles
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Asymmetric N-alkylations of isatins with enals were shown to be feasible via a prolinol-catalyzed iminium activation, and N-alkylated isatins were obtained in good yields and with excellent enantioselectivity. The biologically useful N-alkylated isatins also served as valuable synthetic precursors, and could be readily converted to chiral N-alkylated indole derivatives. The described method provides a novel entry to access optically enriched N-alkylated isatins and indole derivatives. the Partner Organisations 2014.
- Dou, Xiaowei,Yao, Weijun,Jiang, Chunhui,Lu, Yixin
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supporting information
p. 11354 - 11357
(2014/10/16)
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- Novel indoline-2,3-dione derivatives as inhibitors of aminopeptidase N (APN)
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Aminopeptidase N (APN/CD13), as a zinc-containing ectoenzyme, plays a critical role in the process of tumor angiogenesis, invasion and metastasis. Through the docking-based virtual screening of chemical databases and the further activity assay, we discovered that compound 10c exhibits potent and selective inhibitory ability towards APN. In addition, a series of indoline-2,3-dione derivates have been designed and synthesized as APN inhibitors. The results of preliminary activity evaluation showed that compound 12a (IC50 = 0.074 ± 0.0026 μM) exhibited the best inhibitory activity against APN, which could be used for further anticancer agent research.
- Jin, Kang,Zhang, Xiaopan,Ma, Chunhua,Xu, Yingying,Yuan, Yumei,Xu, Wenfang
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p. 2663 - 2670
(2013/06/27)
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- Crystal structure and new approach to spiro[1,3-dioxolane-2,3′- indolin]-2′-one
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The title compounds, spiro[1,3-dioxolane-2,3′-indolin]-2′-one, was synthesized with isatin and 2-chIoroethanol by a intramolecular substitution reaction in the presence of K2C03 for the first time, which avoided the using of H+ as catalyst in traditional synthesis of ketal compounds. The structure of spiro[1,3-dioxolane-2,3′-indolin]-2′-one was studied by X-ray single crystal diffraction, and the two byproducts in the reaction were characterized by H1-NMR, MS spectrums. With these results, the proposed way to spiro[1,3-dioxolane-2,3′-indolin]-2′- one and the two byproducts was brought forward.
- Chen, Gang,Meng, Mei,Tang, Ying,Hao, Xiao-Jiang
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experimental part
p. 137 - 143
(2011/06/27)
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- Radical arylaminomethylation of unactivated alkenes
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Xanthates derived from open chain or cyclic N-chloromethylanllldes are capable of adding to various unactlvated alkenes to give adducts which, In suitable cases, can be made to undergo ring closure onto the aromatic ring. This flexible arylamlnomethylatlon of alkenes allows the rapid synthesis of open chain or polycycllc aniline derivatives.
- Lebreux, Frederic,Quiclet-Sire, Beatrice,Zard, Samir Z.
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supporting information; experimental part
p. 2844 - 2847
(2009/12/06)
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- Enantioselective synthesis of an aziridinomitosane and selective functionalizations of a key intermediate
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An enantioselective synthesis of mitosane core (-)-1 has been achieved. Key steps include a rapid assembly of a key eight-membered-ring intermediate employing ring-closing metathesis. Kinetic resolution of an advanced secondary alcohol was then accomplished by using a peptide-based asymmetric acyl transfer catalyst that was discovered from a parallel screen of catalyst candidates. Optically pure material was then converted to the mitosane core, which was the subject of additional studies on the selective modification to produce several substituted compounds containing a mitosane ring system.
- Papaioannou, Nikolaos,Blank, Jarred T.,Miller, Scott J.
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p. 2728 - 2734
(2007/10/03)
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- Investigation of the selective reduction of isatin derivatives. Synthesis of α-hydroxyacetophenone derivatives and ethyl spiro-3,3-(ethylenedioxy)-2-hydroxyindoline carboxylates
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The product from the reduction of ethyl spiro-3,3-(ethylenedioxy)-2-oxindole carboxylates (1) using borohydride salts has been found to be dependant upon both solvent and metal ion. With polar solvents and lithium bromide/sodium borohydride, spiro-3,3-(ethylenedioxy)-2-hydroxyindole carboxylates (2) are obtained in high yields whilst [2-(2-hydroxymethyl-[1,3]dioxolan-2-yl)-phenyl]-carbamic acid ethyl esters (3) are obtained using sodium borohydride in less polar solvents.
- Garden, Simon J.,C?rrea, Marilza B.,Pinto, Angelo C.
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p. 7617 - 7621
(2007/10/03)
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- Enantioselective synthesis of a mitosane core assisted by diversity-based catalyst discovery.
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[reaction: see text]. Synthesis of mitosane 1 in optically pure form is reported. A retrosynthetic plan that proceeds through racemic allylic alcohol 3 was carried out. This intermediate served as a test substrate for a rapid screen of a small library (15
- Papaioannou,Evans,Blank,Miller
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p. 2879 - 2882
(2007/10/03)
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- Oral Hypoglycemic Agents. Pyrimidoindoles and Related Compounds
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A series of pyrimidoindoles were synthesized and studied for their hypoglycemic activity following oral administration at standard dose of 100 mg/kg to fed rats.The effect of 10-alkoxyalkyl, 10-alkyl, 10-aryl, and 3,3-dialkyl substitution on the activity of 10-hydroxypyrimidoindoles was investigated.Relative potencies of a number of the most active compounds were defined by three-point dose-response studies.The most potent compounds were those with either 3,3-dimethyl substituents, compounds 21, 22, and 38, or 3,3-spirocyclohexane substituents, compounds 39 and 49. 10-Aminopyrimidoindoles were in general less active than the 10-hydroxy analogues, and potency was further decreased by derivatizing the 10-amino group.The most potent 10-amino derivatives were 57 and 58.
- Cliffe, Ian A.,Lien, Eric L.,Mansell, Howard L.,Steiner, Kurt E.,Todd, Richard S.,et al.
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p. 1169 - 1175
(2007/10/02)
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- Potential anticonvulsants. 11. Synthesis and anticonvulsant activity of spiro[1,3-dioxolane-2,3'-indolin]-2'-ones and structural analogues
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A number of spiro[1,3-dioxolane-2,3'-indolin]-2'-ones were synthesized and tested for anticonvulsant activity in the maximal electroshock seizure (MES) and pentylenetetrazole seizure threshold (sc-Met) tests. 5'-Chlorospiro[1,3-dioxolane-2,3'-indolin]-2'-one was the most active compound in the MES test and had ED50 = 27.97 mg/kg. Structural analogues spiro[1,3-dioxane-2,3'-indolin]-2'-one, spiro[1,3-dithiolane-2,3'-indolin]-2'-one, spiro[indoline-3,2'-[1,3]-oxathiolan]-2-one, and 3,3-dimethoxyindolin-2-one were also evaluated for anticonvulsant activity. Almost all compounds submitted for screening exhibited the ability to protect mice against electrically and chemically induced seizures. The ED50 and TD50 values for some of the title compounds are reported. Anticonvulsant screenings were carried out through NINCDS, NIH.
- Rajopadhye,Popp
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p. 1001 - 1005
(2007/10/02)
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