- Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents
-
The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1-42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1-42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.
- Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Teli, Divya M.,Patel, Kishan B.,Gandhi, Pallav M.,Patel, Sagar P.,Chaudhary, Bharat N.,Shah, Dharti B.,Prajapati, Navnit K.,Patel, Kirti V.,Yadav, Mange Ram
-
p. 3557 - 3574
(2020/11/18)
-
- Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis
-
Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 μM, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.
- Aneja, Babita,Khan, Nashrah Sharif,Khan, Parvez,Queen, Aarfa,Hussain, Afzal,Rehman, Md. Tabish,Alajmi, Mohamed F.,El-Seedi, Hesham R.,Ali, Sher,Hassan, Md. Imtaiyaz,Abid, Mohammad
-
p. 840 - 852
(2019/01/04)
-
- Palladium(II)/N-Heterocyclic Carbene Catalyzed One-Pot Sequential α-Arylation/Alkylation: Access to 3,3-Disubstituted Oxindoles
-
Rationally designed fluorene-based mono- and bimetallic Pd-PEPPSI complexes were synthesized and demonstrated to be effective for the one-pot sequential α-arylation/alkylation of oxindoles. This streamlined approach offers efficient access to functionalized 3,3-disubstituted oxindoles in excellent yields (up to 89%) under mild reaction conditions.
- Reddy Panyam, Pradeep Kumar,Ugale, Bharat,Gandhi, Thirumanavelan
-
supporting information
p. 7622 - 7632
(2018/06/22)
-
- Synthesis of 7-halo indoles (by machine translation)
-
The present invention relates to synthesis of 7? Halo indole method, comprising the steps of:O-halogenated aniline, chloral hydrate and hydroxylamine hydrochloride by the Sandmeyer reaction to synthesize 7? halogenating isatin ; 7? halogenating isatin dissolved with an organic solvent, in the reducing agent by reduction reaction under the conditions of 7? Halo indole, the reducing agent is an alkali metal borohydride system, four system adopts, lithium hydride system or triethyl silane system. The beneficial effect of the invention is:in order to O-halogenated aniline and the chloral hydrate is, hydroxylamine hydrochloride as raw materials, by the Sandmeyer shall synthesis method for preparing compositions b isonitroso 7? halogenating isatin, and then by further reduction and system reduction to prepare 7? Halo indole; by the 7? Preparation halogenating isatin 7? Halo indole method, the raw material is easy to obtain, low price, higher process yield, the product purity is good, simple operation, and the like, is suitable for batch preparation 7? Halo indole. (by machine translation)
- -
-
Paragraph 0018
(2017/01/12)
-
- A cinchona alkaloid catalyzed enantioselective sulfa-Michael/aldol cascade reaction of isoindigos: Construction of chiral bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters
-
A cinchona alkaloid catalyzed diastereoselective and enantioselective sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and isoindigos has been successfully developed to afford the highly congested bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters in high yields (up to 91%), excellent diastereoselectivities (up to >20 : 1 dr), and good enantioselectivities (up to 98% ee). Some synthetic transformations of the reaction products were also studied.
- Gui, Yong-Yuan,Yang, Jian,Qi, Liang-Wen,Wang, Xiao,Tian, Fang,Li, Xiao-Nian,Peng, Lin,Wang, Li-Xin
-
supporting information
p. 6371 - 6379
(2015/06/08)
-
- 7-SUBSTITUTED INDIRUBIN-3'OXIMES AND THEIR APPLICATIONS
-
The invention relates to new 3′-, 7-substituted-indirubins of formula (I) wherein R represents N—OH, N—O-alkyl or N—O—CO-alkyl, NO—(Ra)n1-Het, N—O—(Y)n1—NRaRb, N—O—CO—N(RbRc), ra
- -
-
Page/Page column 5
(2011/01/05)
-
- Synthesis of insecticidal fluorinated anthranilic diamides
-
A series of highly active fluorinated anthranilic diamide insecticides have been prepared and their biological activity assessed on two aphid species in the search for systemically active compounds that control Hemiptera. In addition, we have demonstrated a new synthesis of N-aryl 3-fluoropyrazoles.
- Clark, David A.,Lahm, George P.,Smith, Ben K.,Barry, James D.,Clagg, Don G.
-
p. 3163 - 3170
(2008/09/20)
-
- Methods and Compositions for Selectin Inhibition
-
The present teachings relate to novel compounds of formula I: wherein the constituent variables are as defined herein. Compounds of the present teachings can act as antagonists of the mammalian adhesion proteins known as selecting. Methods for treating or preventing selectin-mediated disorders are provided, which include administration of these compounds in a therapeutically effective amount.
- -
-
Page/Page column 23
(2008/12/04)
-
- QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
-
The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.
- -
-
-
- Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists
-
Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.
- Kaila, Neelu,Janz, Kristin,DeBernardo, Silvano,Bedard, Patricia W.,Camphausen, Raymond T.,Tam, Steve,Tsao, Desirée H.H.,Keith Jr., James C.,Nickerson-Nutter, Cheryl,Shilling, Adam,Young-Sciame, Ruth,Wang, Qin
-
-
- 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H] quinoline-4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
-
P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
- Kaila, Neelu,Janz, Kristin,Huang, Adrian,Moretto, Alessandro,DeBernardo, Silvano,Bedard, Patricia W.,Tam, Steve,Clerin, Valerie,Keith Jr., James C.,Tsao, Desirée H.H.,Sushkova, Natalia,Shaw, Gray D.,Camphausen, Raymond T.,Schaub, Robert G.,Wang, Qin
-
-
- Process for preparing isatins with control of side-product formation
-
Methods and kits for preventing or minimizing the formation of isatin oximes during formation of an isatin from an isonitrosoacetanilide are provided. Also provided are methods and kits for preventing or minimizing the formation of isatin oxime impurities
- -
-
Page/Page column 7
(2008/06/13)
-
- 3′-substituted 7-halogenoindirubins, a new class of cell death inducing agents
-
Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis and biological evaluation of 3′-substituted 7-halogenoindirubins. M
- Ferandin, Yoan,Bettayeb, Karima,Kritsanida, Marina,Lozach, Olivier,Polychronopoulos, Panagiotis,Magiatis, Prokopios,Skaltsounis, Alexios-Leandros,Meijer, Laurent
-
p. 4638 - 4649
(2007/10/03)
-
- Condensed pyrazole derivatives, process for producing the same and use thereof
-
Novel pharmaceutical compositions for inhibiting Th2-selective immune response and pharmaceutical compositions for inhibiting cyclooxygenase comprising condensed pyrazole derivatives represented by the general formula (I): or salts thereof.
- -
-
-
- A General Method for the Synthesis of Isatins: Preparation of Regiospecifically Functionalized Isatins from Anilines
-
A new method has been developed for regiospecific conversion of substituted anilines to isatins.The method utilizes the reaction of an ortho-lithiated, protected aniline derivative with diethyl oxalate to furnish an α-ketoester.Hydrolytic deprotection of the amino moiety is accompanied by cyclization to provide the isatin.
- Hewawasam, Piyasena,Meanwell, Nicholas A.
-
p. 7303 - 7306
(2007/10/02)
-
- Antimicrobial activity of fluorinated 1,2-benzisothiazol-3(2H)-ones and 2,2'-dithiobis(benzamides)
-
Fluoro and trifluoromethyl derivatives of 1,2-benzisothiazol-3(2H)-ones and the 2,2'-dithiobis(benzamides) have been prepared and their antifungal and antibacterial activity evaluated. Several compounds were found highly active against fungi and Gram-positive microorganisms and a few derivatives displayed some activity against Gram-negative strains. Structure-activity relationships are proposed.
- Carmellino,Pagani,Pregnolato,Terreni,Pastoni
-
p. 743 - 751
(2007/10/02)
-
- Biological activities and quantitative structure-activity relationships of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones as aldose reductase inhibitors
-
A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'- halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'- chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure- activity relationships in this series are also discussed.
- Yamagishi,Yamada,Ozaki,Asao,Shimizu,Suzuki,Matsumoto,Matsuoka,Matsumoto
-
p. 2085 - 2094
(2007/10/02)
-
- Synthetic Entries to 6-Fluoro-7-substituted Indole Derivatives
-
Three practical synthetic entries of functionalized 6-fluoro-7-substituted indole derivatives were developed in connection with the preparation of 7-fluoro-8-substituted-1,3,4,9-tetrahydropyranoindole-1-acetic acid derivatives 11.The first route, w
- McKittrick, Brian,Failli, Amedeo,Steffan, Robert J.,Soll, Richard M.,Hughes, Philip,et al.
-
p. 2151 - 2163
(2007/10/02)
-
- Certain 1,3-dihydro-1-[heterocyclic)imino]-furo-[3,4-b]quinoline 9-ol compounds having analgesic and anti-inflammatory activity
-
A 4-hydroxy-3-quinoline-carboxamides of the formula STR1 wherein X is in the 5,6,7 or 8-position and is selected from the group consisting of hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 4 carbon atoms, --CH3, --OCF3/su
- -
-
-
- 4-Hydroxy-3-quinoline-carboxylic acid derivatives
-
Novel 4-hydroxy-3-quinoline-carboxamides of the formula STR1 wherein X is in the 5,6,7 or 8-position and is selected from the group consisting of hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 4 carbon atoms, --CF3, --OCF3
- -
-
-
- A VERSATILE AND EFFICIENT PROCESS TO 3-SUBSTITUTED INDOLES FROM ANILINES
-
Borane-mediated reductive elimination of α-thiomethyl-, α-hydroxy-, or α-alkoxy-, α'-substituted oxindoles affords 3-substituted indoles in high yield.Isatins, available via several routes from oxindoles, also afford indoles.
- Wierenga, Wendell,Griffin, John,Warpehoski, Martha A.
-
p. 2437 - 2440
(2007/10/02)
-