- Organocatalytic Asymmetric Synthesis of Cyclic Acetals with Spirooxindole Skeleton
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An organocatalytic asymmetric synthesis of cyclic acetal with spirooxindole skeleton has been developed via a domino reaction between isatin and γ-hydroxy enones. Bifunctional squaramide catalyst with adamantyl motif was found to be the most effective for the cascade reaction. With 10 mol% of the catalyst, the desired products were obtained in 1.8:1 to 9:1 diastereo- and 86% to >99% enantioselectivities from a range of substituted isatins and γ-hydroxy enones. (Figure presented.).
- Shikari, Amit,Mandal, Koushik,Chopra, Deepak,Pan, Subhas Chandra
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supporting information
p. 58 - 63
(2021/11/09)
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- New cell cycle checkpoint pathways regulators with 2-Oxo-indoline scaffold as potential anticancer agents: Design, synthesis, biological activities and in silico studies
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3-Arylidene-2-oxo-indoline derivatives are at the heart of a wide range of clinically, medicinally and biologically important compounds among the 2-oxo-indolines. A number of 3-arylidene-2-oxo-indolines have been approved for clinical application. Accordi
- Abd El-wahab, Hend A.A.,Mansour, Hany S.,Ali, Ahmed M.,El-Awady, Raafat,Aboul-Fadl, Tarek
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- Rongalite-induced transition-metal and hydride-free reductive aldol reaction: a rapid access to 3,3′-disubstituted oxindoles and its mechanistic studies
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A transition-metal and hydride-free reductive aldol reaction has been developed for the synthesis of biologically active 3,3′-disubstituted oxindoles from isatin derivatives using rongalite. In this protocol, rongalite plays a dual role as a hydride-free
- Anugu, Naveenkumar,Golla, Sivaparwathi,Jalagam, Swathi,Kokatla, Hari Prasad
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supporting information
p. 808 - 816
(2022/02/03)
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- Synthesis and Exploration of Abscisic Acid Receptor Agonists Against Dought Stress by Adding Constraint to a Tetrahydroquinoline-Based Lead Structure
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New oxotetrahydroquinolinyl- and oxindolinyl sulfonamides interacting with RCAR/(PYR/PYL) receptor proteins were identified as lead structures against drought stress in crops starting from protein docking studies of a sulfonamide lead structure, followed by in-depth SAR studies. Optimized five to six step synthetic approaches via substituted amino oxo-tetrahydro-quinolines and amino oxo-indolines as essential intermediates gave access to the envisaged oxo-tetrahydroquinolinyl and oxindolinyl sulfonamides. Whilst oxo-tetrahydroquinolinyl sulfonamides with additional carbon substituents or spiro-cycloalkyl groups exhibited only low to moderate target affinities, the corresponding spiro-oxindolinyl and oxo-tetrahydroquinolinyl sulfonamides carrying optimized N-substituents revealed strong interactions with RCAR/(PYR/PYL) receptor proteins in Arabidopsis thaliana. Remarkably, the in vitro activity observed for these new compounds was on the same level as observed for the naturally occurring plant hormone in line with strong efficacy against drought stress in-vivo (canola and wheat as broad-acre crops).
- Baltz, Rachel,Bojack, Guido,Dittgen, Jan,Fischer, Christian,Frackenpohl, Jens,Freigang, J?rg,Getachew, Rahel,Grill, Erwin,Helmke, Hendrik,Hohmann, Sabine,Lange, Gudrun,Lehr, Stefan,Porée, Fabien,Schmidt, Jana,Schmutzler, Dirk,Yang, Zhenyu
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p. 3442 - 3457
(2021/06/25)
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- Development of isatin-thiazolo[3,2-a]benzimidazole hybrids as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological and molecular dynamics investigations
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In the current medical era, human health is experiencing numerous challenges, particularly the human malignancies. Therefore, the therapeutic arsenal for these malignancies is to be inexorably enhanced with new treatments that target tumor cells in a selective manner. In this regard, the present work aims at developing a new set of small molecules featuring the privileged isatin scaffold conjugated with a thiazolo[3,2-a]benzimidazole (TBI) motif through a cleavable hydrazide linker (7a-e and 10a-i) as potential anticancer CDK2 inhibitors. The large tricyclic TBI motif is anticipated to achieve a plethora of hydrophobic interactions within the CDK2 binding site. The growth of the two examined cell lines was significantly inhibited by most the prepared hybrids with IC50 ranges; (2.60 ± 1.47–20.90 ± 1.17 μM, against MDA-MB-231) and (1.27 ± 0.06–16.83 ± 0.95 μM, against MCF-7). In particular, hybrids 7a, 7d and 10a displayed potent dual activity against the examined cell lines, and thus selected for further investigations. They exerted a significance alteration in the cell cycle progression, in addition to an apoptosis induction within both MDA-MB-231 and MCF-7 cells. Furthermore, 7a, 7d and 10a displayed potent CDK2 inhibitory action (IC50 = 96.46 ± 5.3, 26.24 ± 1.4 and 42.95 ± 2.3 nM, respectively). The docking simulations unveiled, as expected, the ability of the TBI ring to well-accommodate and establish several hydrophobic interactions within a hydrophobic pocket in the CDK2 binding site. Also, the docking simulations highlighted the significance of incorporation of the hydrazide linker and isatin unsubstituted (NH) functionality in the H-bonding interactions. Interestingly, the most potent CDK2 inhibitor 7d achieved the best binding score (-11.2 Kcal/mole) and formed the most stable complex with CDK2 enzyme (RMSD = 1.24 ?) in a 100 ns MD simulation. In addition, the MM-PBSA calculations ascribed the lowest binding free energy to the 7d–CDK2 complex (?323.69 ± 15.17 kJ/mol). This could be attributed to an incorporation of the 5-OCH3 group that was engaged in an extra hydrogen bonding with key THR14 amino acid residue. Finally, these results suggested hybrid 7d as a good candidate for further optimization as promising breast cancer antitumor agent and CDK2 inhibitor.
- Eldehna, Wagdy M.,El Hassab, Mahmoud A.,Abo-Ashour, Mahmoud F.,Al-Warhi, Tarfah,Elaasser, Mahmoud M.,Safwat, Nesreen A.,Suliman, Howayda,Ahmed, Marwa F.,Al-Rashood, Sara T.,Abdel-Aziz, Hatem A.,El-Haggar, Radwan
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supporting information
(2021/03/15)
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- Development of 2-oindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells
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Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin–indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges132–611 nM compared to IC50 = 4.6 μM for 5FU, against HT-29 and IC50 ranges 37–468 nM compared to IC50 = 1.5 μM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.
- Abdel-Aziz, Hatem A.,Abdulla, maha,Abo-Ashour, mahmoud f.,Ahmad, Rehan,Al-Khayal, Khayal,Al-Rashood, Sara T.,Al-Warhi, Tarfah,Alharbi, Amal,Ayyad, Rezk R.,El-Haggar, Radwan,Eldehna, Wagdy m.
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p. 319 - 328
(2020/12/23)
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- Development of novel isatin–nicotinohydrazide hybrids with potent activity against susceptible/resistant Mycobacterium tuberculosis and bronchitis causing–bacteria
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Joining the global fight against Tuberculosis, the world's most deadly infectious disease, herein we present the design and synthesis of novel isatin-nicotinohydrazide hybrids (5a–m and 9a–c) as promising anti-tubercular and antibacterial agents. The anti-tubercular activity of the target hybrids was evaluated against drug-susceptible M. tuberculosis strain (ATCC 27294) where hybrids 5d, 5g and 5h were found to be as potent as INH with MIC = 0.24 μg/mL, also the activity was evaluated against Isoniazid/Streptomycin resistant M. tuberculosis (ATCC 35823) where compounds 5g and 5h showed excellent activity (MIC = 3.9 μg/mL). Moreover, the target hybrids were examined against six bronchitis causing-bacteria. Most derivatives exhibited excellent antibacterial activity. K. pneumonia emerged as the most sensitive strain with MIC range: 0.49–7.81 μg/mL. Furthermore, a molecular docking study has proposed DprE1 as a probable enzymatic target for herein reported isatin-nicotinohydrazide hybrids, and explored the binding interactions within the vicinity of DprE1 active site.
- Elsayed, Zainab M.,Eldehna, Wagdy M.,Abdel-Aziz, Marwa M.,El Hassab, Mahmoud A.,Elkaeed, Eslam B.,Al-Warhi, Tarfah,Abdel-Aziz, Hatem A.,Abou-Seri, Sahar M.,Mohammed, Eman R.
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p. 384 - 393
(2021/01/13)
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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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- Design and synthesis of novel isatin-based derivatives targeting cell cycle checkpoint pathways as potential anticancer agents
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In recent years, cell cycle and checkpoint pathways regulation are offering new therapeutic approaches against cancer. Isatin, is a well exploited scaffold in the anticancer domain. Accordingly, the current work describes the design and synthesis of two series of (Z)-3-substituted-2-(((E/Z)-5-substituted-2-oxo-1-substituted-indolin-3-ylidene)hydrazinylidene)-thiazolidin-4-ones, 4(a-s) and (E/Z)-1-substituted-3-(((Z)-3-substituted-4-methylthiazol-2(3H)-ylidene)hydrazineylidene)-5-substituted-indolin-2-ones, 5(a-s). The structures of the synthesized molecules were confirmed by spectral and elemental methods of analyses. Pure diastereomers were further identified with 1H-1H-NOESY and confirmed with X-ray crystallography. The target compounds were tested in vitro for their cytotoxicity against three human epithelial cell lines, liver (HepG2), breast (MCF-7), and colon (HT-29) in addition to the diploid human normal cells (WI-38) compared to doxorubicin as a reference drug. Variable cytotoxic effects (IC50 3.29–100 ?μmol) were reported on the three cancer cell lines with pronounced selectivity compared to the normal one WI-38. The potency of the most active compounds, 4o, 4s, 5e, 5f, 5l, 5m and 5o (IC50 3.29–9.92 ?μmol), in both series associated with the (Z) configurations of N = thiazolidin/ene or one, however, the configuration of the N = isatin moiety seemed to be of no importance to the activity. The tested compounds were grouped for their possible mechanism of action into 4 categories. Compound 4o with no apparent effect on all genes examined. Compounds 4s and 5o affected all genes investigated and seem to have multiple cellular targets; induced the expression of p53 and caspases, and downregulated that of CDK1. Compounds 5l and 5m directly elevated the expression of initiator and effector caspases without going through p53 pathway. Finally, compounds 5e and 5f elevated the expression of p53 and inhibited CDK1. Compounds 4s, 5e, 5f, 5l, 5m, and 5o caused a significant elevation in the activity of cleaved caspase 3 as well. Docking studies on CDK1 revealed that the active molecules bind to the tested enzyme by the same manner of the co-crystallized ligands and the isatin-thiazoldinone/ene scaffold is essential for binding of these molecules.
- Yousef, Mohamed A.,Ali, Ahmed M.,El-Sayed, Wael M.,Quayed, Wesam S.,Farag, Hassan H.A.,Aboul-Fadl, Tarek
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- Annulation reaction of cyclic pyridinium ylides with: In situ generated azoalkenes for the construction of spirocyclic skeletons
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Two new types of cyclic pyridinium ylides were designed and further used in reactions with azoalkenes to access structurally diverse spirocyclic compounds. A range of spiropyrazoline oxindoles could be smoothly obtained in up to 99% yield via a [4 + 1] annulation process with oxindole 3-pyridinium ylides as C1 synthons. Similarly, a series of spiropyrazoline indanones could be prepared with indanone 2-pyridinium ylides as C1 synthons. This work represents the first example of cyclic pyridinium ylides as C1 synthons for the efficient construction of spirocyclic compounds.
- Quan, Bao-Xue,Yuan, Wei-Cheng,Zhang, Ming-Liang,Zhang, Xiao-Mei,Zhao, Jian-Qiang,Zhou, Ming-Qiang,Zhuo, Jun-Rui
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supporting information
p. 1886 - 1891
(2020/03/23)
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- Design, synthesis, and biological evaluation of 1,2,3-triazole-linked triazino[5,6-b]indole-benzene sulfonamide conjugates as potent carbonic anhydrase I, II, IX, and XIII inhibitors
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A series of 1,2,3-triazole-linked triazino[5,6-b]indole-benzene sulfonamide hybrids (6a– 6o) was synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against the human (h) isoforms hCA I, II, XIII (cytosolic isoforms), and hCA IX (transmembrane tumor-associated isoform). The results revealed that the compounds 6a–6o exhibited Ki values in the low to medium nanomolar range against hCA II and hCA IX (Kis ranging from 7.7 nM to 41.3 nM) and higher Ki values against hCA I and hCA XIII. Compound 6i showed potent inhibition of hCA II (Ki = 7.7nM), being more effective compared to the standard inhibitor acetazolamide (AAZ) (Ki = 12.1 nM). Compounds 6b and 6d showed moderate activity against hCA XIII (Ki= 69.8 and 65.8 nM). Hence, compound 6i could be consider as potential lead candidate for the design of potent and selective hCA II inhibitors.
- Angeli, Andrea,Arifuddin, Mohammed,Biswas, Rashmita,Chinchilli, Krishna Kartheek,Korra, Laxman Naik,Supuran, Claudiu T.,Thacker, Pavitra S.
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- Synthesis, biological evaluation and in silico studies of certain oxindole–indole conjugates as anticancer CDK inhibitors
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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 μM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.
- Abdel-Aziz, Hatem A.,Al-Ansary, Ghada H.,Al-Warhi, Tarfah,Aljaeed, Nada,Ayyad, Rezk R.,El Kerdawy, Ahmed M.,Eldehna, Wagdy M.,Ismael, Omnia E.
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- Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents
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Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7–86.1 nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192–239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC50 = 7.43 ± 0.28 and 12.90 ± 0.34 μM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents.
- Eldehna, Wagdy M.,Abo-Ashour, Mahmoud F.,Nocentini, Alessio,El-Haggar, Radwan S.,Bua, Silvia,Bonardi, Alessandro,Al-Rashood, Sara T.,Hassan, Ghada S.,Gratteri, Paola,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
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p. 147 - 160
(2018/11/23)
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- Synthesis of isatin based N1-alkylated 3-β-C-glycoconjugated-oxopropylidene oxindoles as potent antiplasmodial agents
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In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by deh
- Thakur, Ravi Kumar,Joshi, Prince,Upadhyaya, Kapil,Singh, Kartikey,Sharma, Gaurav,Shukla, Sanjeev K.,Tripathi, Renu,Tripathi, Rama Pati
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supporting information
p. 448 - 454
(2018/11/25)
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- Organocatalytic double arylation of 3-isothiocyanato oxindoles: Stereocontrolled synthesis of complex spirooxindoles
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Quinones, precursors of aromatic structures, were firstly employed as the electrophiles for the organocatalytic Michael addition/cyclization cascade reaction with versatile 3-isothiocyanato oxindoles. Chiral bifunctional organocatalyst was appropriate for this enantioselective transformation to afford a variety of novel spirooxindoles, possessing a spirocyclic stereocenter adjacent to the aromatic ring, via asymmetric double arylation. These synthesized spirooxindoles are very difficult to access by the reported methods and were obtained in excellent chemical yields with excellent enantioselectivities.
- Zhang, Lin-Lin,Da, Bing-Chao,Xiang, Shao-Hua,Zhu, Shuai,Yuan, Zi-Yun,Guo, Zhen,Tan, Bin
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supporting information
p. 1689 - 1696
(2018/11/25)
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- On the importance of antiparallel π-π Interactions in the solid state of isatin-based hydrazides
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The condensation of N-propyl isatin (1) with different carboxylic acid hydrazides (RCONHNH2 (2-6), R = arene) via sonication was used to synthesize five new hydrazones (7-11). Fully characterized molecular structures were further studied by sin
- Ahmed, Muhammad Naeem,Arif, Maryam,Jabeen, Farah,Khan, Haroon Ahmed,Yasin, Khawaja Ansar,Tahir, Muhammad Nawaz,Franconetti, Antonio,Frontera, Antonio
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p. 8122 - 8131
(2019/06/07)
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- 3-Hydrazinoisatin-based benzenesulfonamides as novel carbonic anhydrase inhibitors endowed with anticancer activity: Synthesis, in vitro biological evaluation and in silico insights
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Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3–65.4 nM) and (11.9–72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.
- Abo-Ashour, Mahmoud F.,Eldehna, Wagdy M.,Nocentini, Alessio,Bonardi, Alessandro,Bua, Silvia,Ibrahim, Hany S.,Elaasser, Mahmoud M.,Kry?tof, Vladimír,Jorda, Radek,Gratteri, Paola,Abou-Seri, Sahar M.,Supuran, Claudiu T.
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- Method for preparing indole-2,3-dione derivatives by catalytic oxidation of microwave copper/peroxyacetic acid
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The invention discloses a method for preparing indole-2,3-dione derivatives by catalytic oxidation of microwave copper/peroxyacetic acid. The method comprises the following steps: a catalytic amount of catalyst copper iodide, indole, a derivative of the indole and peroxyacetic acid are added into a reaction vessel, wherein the indole, the derivative of the indole and the peroxyacetic acid are usedas raw materials, ethanol is used as a solvent, the reaction vessel is placed into a microwave reaction instrument, a reaction is performed at certain temperature and power, after a certain time, reduced-pressure concentration is performed, and a product is purified by column chromatography. The method provided by the invention is a method having novel raw materials, simple operation and high efficiency used for preparing a benzimidazole derivative; and compared with the prior art, the method provided by the invention has an obviously-accelerated reaction speed than that under conventional heating, mild reaction conditions, simple operation, a high yield, safety, low costs and environmental protection.
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Paragraph 0024; 0027
(2018/09/08)
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- Reactivity of spiroanthraceneoxazolidines with cyclopropanes: An approach to the oxindole alkaloid scaffold
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The reaction of N-methylspiro[anthracene-oxazolidine] with spiro[cyclopropane-3,3′-indolin]-2-ones in the presence of MgI2 formed the corresponding spiro[pyrrolidine-3,3′-indolin]-2-ones in 42–65% yields. The use of N-benzylspiro[anthracene-oxazolidine] in this reaction led to the formation of a mixture of the corresponding N-methyl- and N-benzylpyrrolidines.
- Buev, Evgeny M.,Moshkin, Vladimir S.,Sosnovskikh, Vyacheslav Y.
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supporting information
p. 3409 - 3412
(2018/08/20)
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- Novel [(3-indolylmethylene)hydrazono]indolin-2-ones as apoptotic anti-proliferative agents: design, synthesis and in vitro biological evaluation
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On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a–r, 9a–f and 11a–c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC50=1.04 μM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.
- Eldehna, Wagdy M.,Abo-Ashour, Mahmoud F.,Ibrahim, Hany S.,Al-Ansary, Ghada H.,Ghabbour, Hazem A.,Elaasser, Mahmoud M.,Ahmed, Hanaa Y. A.,Safwat, Nesreen A.
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p. 686 - 700
(2018/04/02)
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- Novel hydrazido benzenesulfonamides-isatin conjugates: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies
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As a part of our ongoing efforts towards developing novel carbonic anhydrase inhibitors based on the isatin moiety, herein we report the synthesis and biological evaluation of novel sulfonamides (5a-h, 10a-g and 11a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with KIs in the range of 671.8: 3549.5 nM, hCA II in the range of 36.8: 892.4 nM; hCA IX in the range of 8.9: 264.5 nM, whereas hCA XII in the range of 9.0: 78.1 nM. In particular, compound 10b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2 nM, respectively). Molecular docking studies carried out for compound 10b within the hCA II, IX and XII active sites allowed us to rationalize the obtained inhibition results.
- Abo-Ashour, Mahmoud F.,Eldehna, Wagdy M.,Nocentini, Alessio,Ibrahim, Hany S.,Bua, Silvia,Abou-Seri, Sahar M.,Supuran, Claudiu T.
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- Copper-catalyzed aerobic oxidative intramolecular amidation of 2-aminophenylacetylenes: A domino process for the synthesis of isatin
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A novel CuI-catalyzed oxidative amidation of 2-aminophenylacetylenes leading to the formation of isatins by using open air as an oxygen source has been developed. The reaction proceeded smoothly and provided a variety of isatin derivatives in good yields. The advantages of this one-pot reaction protocol include the use of a green oxidant, low-price catalyst and facile conditions, and easy handling.
- Salvanna,Ramesh, Perla,Santosh Kumar,Das, Biswanath
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p. 13754 - 13759
(2017/11/27)
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- USE OF SUBSTITUTED DIHYDROOXINDOLYLSULFONAMIDES, OR THE SALTS THEREOF, FOR INCREASING THE STRESS TOLERANCE OF PLANTS
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The invention relates to the use of substituted dihydrooxindolylsulfonamides or salts thereof of the formula (I) where the radicals in the general formula (I) correspond to the definitions given in the description, for enhancing stress tolerance in plants to abiotic stress, and/or for increasing plant yield.
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Paragraph 0134
(2016/09/12)
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- Synthesis and evaluation of in?vivo antioxidant, in?vitro antibacterial, MRSA and antifungal activity of novel substituted isatin N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazones
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Some new isatin N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazones 4a-t with different substituents at 1-, 5- and 7-positions of isatin ring have been synthesized by reaction of N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazide 2 with corresponding isatins 3a-t. Compounds 4a-t were evaluated in?vivo for antioxidant activity and in?vitro for anti-microorganism activities. The MIC values were found for Gram positive bacteria (MIC?=?1.56–6.25?μM), for Gram negative bacteria (MIC?=?12.5?μM), and for fungi Aspergillus niger (MIC?=?3.12–12.5?μM), Fusarium oxysporum (MIC?=?6.25–12.5?μM) and Saccharomyces cerevisiae (MIC?=?6.25–12.5?μM). Regarding the antioxidant activity, the SOD, GHS-Px and catalase activities of 4c-i and 4m-r were MIC?=?10.57–10.85, 0.27–0.93 and 345.45–399.75 unit/mg protein, respectively. Compounds 4e-h had MIC values of 0.78, 1.56, and 3.12?μM for three clinical MRSA isolates. Compound 4e showed the selective cytotoxic effects against some cancer (LU-1, HepG2, MCF7, P338, SW480, KB) cell lines and normal fibroblast cell line NIH/3T3.
- Thanh, Nguyen Dinh,Giang, Nguyen Thi Kim,Quyen, Tran Ha,Huong, Doan Thi,Toan, Vu Ngoc
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p. 532 - 543
(2016/08/12)
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- Design and synthesis of 3-substituted indolin-2-one derivatives with methyl (e)-2-(3-Methoxy) acrylate moiety
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In this article, fifteen indolin-2-one derivatives with methyl (E)-2-(3-methoxy)acrylate group were designed and synthesized. The structures of target compounds were confirmed by 1H NMR, IR and HR-MS spectra analysis.
- Luo, Xi,Zhang, Yi-Ying,Wang, Yu-Liang
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p. 2911 - 2916
(2015/12/11)
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- Triazino indole-quinoline hybrid: A novel approach to antileishmanial agents
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A novel series of 1,2,4-triazino-[5,6b]indole-3-thione covalently linked to 7-chloro-4-aminoquinoline have been synthesized and evaluated for their in vitro activity against extracellular promastigote and intracellular amastigote form of Leishmania donovani. Among all tested compounds, compounds 7a and 7b were found to be the most active with IC50 values 1.11, 0.36 μM and selectivity index (SI) values 67, >1111, respectively, against amastigote form of L. donovani which is several folds more potent than the standard drugs, miltefosine (IC50 = 8.10 μM, SI = 7) and sodium stibo-gluconate (IC50 = 54.60 μM, SI ≥ 7).
- Sharma, Rashmi,Pandey, Anand Kumar,Shivahare, Rahul,Srivastava, Khushboo,Gupta, Suman,Chauhan, Prem M.S.
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p. 298 - 301
(2015/06/01)
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- Eco-friendly chemoselective N-functionalization of isatins mediated by supported KF in 2-MeTHF
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A sustainable, efficient method for the chemoselective N-functionalization of isatins based on the use of KF-Celite in 2-methyltetrahydrofuran is reported. Notably, the protocol allows reactions with a wide range of electrophiles such as alkyl halides, is
- Mamuye, Ashenafi Damtew,Monticelli, Serena,Castoldi, Laura,Holzer, Wolfgang,Pace, Vittorio
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supporting information
p. 4194 - 4197
(2015/08/11)
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- Novel indolin-2-one-substituted methanofullerenes bearing long N-alkyl chains: Synthesis and application in bulk-heterojunction solar cells
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An easy, high-yield and atom-economic procedure of a C60 fullerene modification using a reaction of fullerene C60 with N-alkylisatins in the presence of tris(diethylamino)phosphine to form novel long-chain alkylindolinone-substituted methanofullerenes (AIMs) is described. Optical absorption, electrochemical properties and solubility of AIMs were studied. Poly(3-hexylthiophene-2,5-diyl) (P3HT)/AIMs solar cells were fabricated and the effect of the AIM alkyl chain length and the P3HT:AIM ratio on the solar cell performance was studied. The power conversion efficiencies of about 2% were measured in the P3HT/AIM devices with 1:0.4 P3HT:AIM weight ratio for the AIMs with hexadecyl and dodecyl substituents. From the optical and AFM data, we suggested that the AIMs, in contrast to [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), do not disturb the P3HT crystalline domains. Moreover, the more soluble AIMs do not show a better miscibility with the P3HT crystalline phase.
- Romanova, Irina P.,Bogdanov, Andrei V.,Izdelieva, Inessa A.,Trukhanov, Vasily A.,Shaikhutdinova, Gulnara R.,Yakhvarov, Dmitry G.,Latypov, Shamil K.,Mironov, Vladimir F.,Dyakov, Vladimir A.,Golovnin, Ilya V.,Paraschuk, Dmitry Yu,Sinyashin, Oleg G.
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p. 1121 - 1128
(2014/06/09)
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- Triazino indole-quinoline hybrid: A novel approach to antileishmanial agents
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A novel series of 1,2,4-triazino-[5,6b]indole-3-thione covalently linked to 7-chloro-4-aminoquinoline have been synthesized and evaluated for their in vitro activity against extracellular promastigote and intracellular amastigote form of Leishmania donovani. Among all tested compounds, compounds 7a and 7b were found to be the most active with IC50 values 1.11, 0.36 μM and selectivity index (SI) values 67, >1111, respectively, against amastigote form of L. donovani which is several folds more potent than the standard drugs, miltefosine (IC50 = 8.10 μM, SI = 7) and sodium stibo-gluconate (IC50 = 54.60 μM, SI ≥ 7).
- Sharma, Rashmi,Pandey, Anand Kumar,Shivahare, Rahul,Srivastava, Khushboo,Gupta, Suman,Chauhan, Prem M.S.
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p. 298 - 301
(2014/01/17)
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- ISATIN COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT OF DEGENERATIVE DISEASES AND DISORDERS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of degenerative diseases and disorders.
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Paragraph 0158; 0159; 0160
(2014/09/30)
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- Copper-catalyzed tandem oxidative cyclization of arylacetamides: Efficient access to N-functionalized isatins
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An efficient copper-catalyzed synthesis of N-substituted isatins has been developed in good yields from easily accessible arylacetamides. A wide range of electronically and structurally varied nitrogen fragments could be assembled through this tandem C-O/C-N bond-forming process by tuning the reaction conditions.
- Sun, Jie,Liu, Bingxin,Xu, Bin
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p. 5824 - 5827
(2013/05/09)
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- Cu(i)-catalyzed intramolecular oxidative C-H amination of 2-aminoacetophenones: A convenient route toward isatins
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2-Aminoaryl methyl ketones undergo intramolecular oxidative C-H amination to give the corresponding substituted isatins under an oxygen atmosphere in the presence of [CuI(bpy)]2. The Royal Society of Chemistry 2013.
- Huang, Pang-Chi,Gandeepan, Parthasarathy,Cheng, Chien-Hong
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supporting information
p. 8540 - 8542
(2013/09/23)
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- Synthesis of 1-substituted 4(1H)-quinazolinones under solvent-free conditions
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(Chemical Equation Presented) Heating a mixture of 2-(N-alkylamino)benzoic acids, triethyl orthoformate, and ammonium acetate under solvent-free conditions generated 1-substituted 4(1H)- quinazolinones in 73-99% yields. Moreover, a possible reaction pathway was proposed. Copyright Taylor & Francis Group, LLC.
- Wang, Yao,Zhang, Mei,Cao, Shengli,Lin, Huihui,Gao, Man,Li, Zhongfeng
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experimental part
p. 2715 - 2727
(2012/07/14)
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- INDOLINONE COMPOUND
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[Problems] A compound, which is useful as an active ingredient for a pharmaceutical composition, for example a pharmaceutical composition for treating constipation-type irritable bowel syndrome, atonic constipation and/or functional gastrointestinal disorder, is provided. [Means for Solution] The present inventors have extensively studied compounds having TRPA1 channel activation activity, and confirmed that an indolinone compound has a TRPA1 channel activation activity, and thus completed the present invention. The indolinone compound of the present invention has a TRPA1 channel activation activity and can be used as an active ingredient of a pharmaceutical composition for preventing and/or treating constipation-type irritable bowel syndrome, atonic constipation and/or functional gastrointestinal disorder or the like.
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Page/Page column 24
(2010/12/30)
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- Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building
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Tuberculosis (TB) remains among the world's great public health challenges. Worldwide resurgence of TB is due to two major problems: the AIDS epidemic, which started in the mid-1980s, and the outbreak of multidrug resistant (MDR) TB. Thus, there is an urgent need for anti-TB drugs with enhanced activity against MDR strains. In recent years, Schiff bases of 1H-indole-2,3-diones are reported to exhibit anti-TB activity. On the other hand, several quinolone antibacterial agents have been examined as inhibitors of TB, as well as other mycobacterial infections. Accordingly, the current work involved design and synthesis of Schiff bases of nalidixic acid carbohydrazide and isatin derivatives (5,6a-f and 7,8a-c). Structures of the synthesized derivatives were confirmed on the bases of spectral methods of analyses. Anti-TB activity of the synthesized derivatives was investigated against four Mycobacterium strains: Mycobacterium intercellulari, Mycobacterium xenopi, Mycobacterium cheleneo and Mycobacterium smegmatis. Modest anti-TB activity was observed within the investigated compounds, however, compound 5f revealed potent anti-TB activity with MIC 0.625 μg/ml, which is 20 times greater than the reference drug isoniazid, INH, (MIC = 12.5 μg/ml). A hypothetical pharmacophore model was built using Molecular Operating Environment (MOE) program and 10 compounds structurally related to the synthesized ones with reported anti-TB activity. The Pharmacophoric model built revealed the necessity of the following pharmacophoric features for anti-TB activity: aromatic center, hydrogen bond acceptor/metal ligator center, hydrogen bond donor center and aromatic center/hydrophobic area. Theses features were consistent with the found anti-TB activity of the tested compounds.
- Aboul-Fadl, Tarek,Bin-Jubair, Fayzah A.S.,Aboul-Wafa, Omima
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scheme or table
p. 4578 - 4586
(2010/10/19)
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- HYDRAZONE MODULATORS OF CANNABINOID RECEPTORS
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Hydrazone compounds which modulate cannabinoid receptors are presented. Pharmaceutical compositions containing these compounds, methods of using these compounds as modulators of cannabinoid receptors and processes for synthesizing these compounds are also described herein.
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Page/Page column 45, 46-47
(2009/03/07)
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- Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain
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There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [35S]GTP-γ-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.
- Diaz, Philippe,Xu, Jijun,Astruc-Diaz, Fanny,Pan, Hao-Min,Brown, David L.,Naguib, Mohamed
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supporting information; experimental part
p. 4932 - 4947
(2009/07/11)
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- Selective photo-reduction of 1-alkylisatins in degassed alcoholic solutions
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Irradiation of 1-alkylisatins (1) in degassed alcohols afforded 1-alkyl-3-hydroxyoxindoles (2) and 1-alkyloxindoles (3) as chemoselective photoproducts.
- Tatsugi, Jiro,Ikuma, Kenji,Izawa, Yasuji
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- Novel Dyestuffs Containing Dicyanomethylidene Groups
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Several series of novel compounds have been prepared containing dicyanomethylidene groups including 1-alkyl-3-dicyanomethylideneindol-2-ones and 6,6-dicyanofulvenes.Their visible absorption properties are recorded and discussed.
- Katritzky, Alan R.,Fan, Wei-Qiang,Liang, De-Sheng,Li, Qiao-Ling
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p. 1541 - 1546
(2007/10/02)
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