- Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database
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The inhibition of the enzyme acetylcholinesterase (AChE) increases the levels of the neurotransmitter acetylcholine and symptomatically improves the affected cognitive function. In the present study, we searched for novel AChE inhibitors by docking-based virtual screening of the standard lead-like set of ZINC database containing more than 6 million small molecules using GOLD software. The top 10 best-scored hits were tested in vitro for AChE affinity, neurotoxicity, GIT and BBB permeability. The main pharmacokinetic parameters like volume of distribution, free fraction in plasma, total clearance, and half-life were predicted by previously derived models. Nine of the compounds bind to the enzyme with affinities from 0.517 to 0.735 μM, eight of them are non-toxic. All hits permeate GIT and BBB and bind extensively to plasma proteins. Most of them are low-clearance compounds. In total, seven of the 10 hits are promising for further lead optimisation. These are structures with ZINC IDs: 00220177, 44455618, 66142300, 71804814, 72065926, 96007907, and 97159977.
- Doytchinova, Irini,Atanasova, Mariyana,Valkova, Iva,Stavrakov, Georgi,Philipova, Irena,Zhivkova, Zvetanka,Zheleva-Dimitrova, Dimitrina,Konstantinov, Spiro,Dimitrov, Ivan
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- ACIDITIES OF 1-INDOLYLACETIC AND CARBAZOLACETIC ACIDS. INDUCTIVE CONSTANTS OF INDOLYL AND CARBAZOLYL GROUPS
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The pKa values of 1-indolylacetic, 3-(9-ethyl)carbyzolylacetic, and a number of 3,6-disubstituted 9-carbazolylacetic acids in aqueous ethanol solutions were determined by potentiometry.The inductive constants of the corresponding heterocyclic fragments were calculated from the values obtained.It is shown that annelation of the benzene ring with the pyrrole ring of indole gives rise to a decrease in the negative inductive effect of the heteroring.A linear relationship between the acidic properties of carbazole and the corresponding 9-carbazolylacetic acids was established.
- Filimonov, V. D.,Sukhoroslova, M. M.,Novikov, V. T.,Vidyagina, T. V.
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- TOTAL SYNTHESIS AND STEREOCHEMICAL REASSIGNMENT OF THE INDOLE ALKALOID VINOXINE
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The first total synthesis of the indole alkaloid vinoxine and the reassignment of the relative configuration at carbon-16 in this alkaloid is reported.
- Bosch, Joan,Bennasar, M.-Lluisa,Zulaica, Ester,Feliz, Miguel
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- Crystal structure and DFT studies of (E)-1-(4-fluorophenyl)-3-(1H-indol-1-yl)-4-styrylazetidin-2-one
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An unprecedented diasterospecific synthesis of (E)-1-(4-fluorophenyl)-3-(1H-indol-1-yl)-4-styrylazetidin-2-one (3) from Staudinger [2 + 2] cycloaddition reaction between (E)-4-fluoro-N-((E)-3-phenylallylidene)aniline (1) and indole ketene is herein described. The single crystal X-ray structure confirmed that compound 3 (C25H19FN2O) crystallizes in the monoclinic space group C2/c, with Z = 8, and unit cell parameters; a = 32.0225 (5) ?, b = 7.39970 (10) ?, c = 17.4100 (2) ?, β = 108.3010 (10)°, V = 3916.75 (10) ?3, Z = 8. Crystal structure 3 shows the absolute cis configuration of the molecule to be C9 (S) and C10 (R). In addition, the structural parameters (bond lengths, bond angles, and torsion angles) and electronic properties of 3 were computed using the B3LYP/6-31 + G (d,p) and M06-2X/6-31 + G (d,p) basis set in ground state. A good correlation (R2 = 0.9989) between the experimental and theoretical parameters was achieved.
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- Br?nsted Acid-Promoted Cyclodimerization of Indolyl Ketones: Construction of Indole Fused-Oxabicyclo[3.3.1]nonane and -Cyclooctatetraene Ring Systems
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A Br?nsted acid-promoted cyclodimerization of C(3)-, C(2)-, or N(1)-substituted indole ketone derivatives is described. A wide range of structurally diverse bisindole fused-9-oxabicyclo[3.3.1]nonane and bisindole fused-cyclooctatetraene (COT) derivatives can be prepared in good to high yields with high efficiency.
- Zhao, Lang,Yan, Zhi-Hua,Tang, Shuai,Wei, Zhong-Lin,Liao, Wei-Wei
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- Discovery of a novel and potent inhibitor with differential species-specific effects against NLRP3 and AIM2 inflammasome-dependent pyroptosis
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The NLRP3 inflammasome, which regulated a proinflammatory programmed cell death form termed pyroptosis, is involved in the pathological process of various human diseases, such as multiple sclerosis, type 2 diabetes, and gout. Thus, compounds inhibiting activation of the NLRP3 inflammasome can be promising treatments for these diseases. In this study, we conducted a phenotypic screening against NLRP3-dependent pyroptosis and discovered the hit compound 1, which showed moderate antipyroptotic activity. Chemistry efforts to improve potency of 1 resulted in a novel compound 59 (J114), which exhibited a half-maximal inhibitory concentration (IC50) of 0.077 ± 0.008 μM against cell pyroptosis. Interestingly, unlike all pyroptosis inhibitors currently reported, the activity of J114 showed significant differences in human- and mouse-derived cells. The IC50 of J114-mediated inhibition of IL-1β secretion by human THP-1 macrophages was 0.098 μM, which was nearly 150-fold and 500-fold more potent than that of J774A.1 (14.62 μM) and bone marrow-derived macrophages (BMDMs) (48.98 μM), respectively. Further studies showed that J114 displayed remarkable inhibitory activity against NLRP3- and AIM2-but not NLRC4-dependent activation of caspase-1 and the release of IL-1β in human THP-1 macrophages. Mechanistically, J114 disturbed the interaction of NLRP3 or AIM2 with the adaptor protein ASC and inhibited ASC oligomerization. Overall, our study identified a unique molecule that inhibits NLRP3 and AIM2 inflammasome activation and has species differences, which is worthy of further research to understand the differential regulation of the NLRP3 and AIM2 inflammasomes in humans and mice.
- Bin, Huachao,Cao, Zhixing,Chen, Pei,Jiao, Yan,Li, Linli,Lin, Guifeng,Lin, Wanting,Mu, Bo,Nan, Jinshan,Pan, Shulei,Pan, Zhiling,Wang, Falu,Xia, Anjie,Yang, Shengyong,Yang, Shunhua,Zhang, Shanshan,Zhang, Yun,Zhou, Nenghua
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- Chemospecific Cyclizations of α-Carbonyl Sulfoxonium Ylides on Aryls and Heteroaryls
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The functionalization of aryl and heteroaryls using α-carbonyl sulfoxonium ylides without the help of a directing group has remained so far a neglected area, despite the advantageous safety profile of sulfoxonium ylides. Described herein are the cyclizations of α-carbonyl sulfoxonium ylides onto benzenes, benzofurans and N-p-toluenesulfonyl indoles in the presence of a base in HFIP, whereas pyrroles and N-methyl indoles undergo cyclization in the presence of an iridium catalyst. Significantly, these two sets of conditions are chemospecific for each groups of substrates.
- Clare, Daniel,Dobson, Benjamin C.,Inglesby, Phillip A.,A?ssa, Christophe
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supporting information
p. 16198 - 16202
(2019/11/03)
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- SUBSTITUTED BENZOXAZINE AND RELATED COMPOUNDS
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The present invention relates to compounds including but not limited to of any one of formulas Ia, Ib, IIa, IIb, IIIa, IIIb, and IV to VI, VIIa, VIIb, VIIIa, VIIIb and VIIIc as described herein and their tautomers and/or pharmaceutically acceptable salts, compositions, and methods of uses thereof.
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Paragraph 0546
(2016/11/28)
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- SUBSTITUTED BENZOXAZINE AND RELATED COMPOUNDS
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The present invention relates to compounds including but not limited to of any one of formulas Ia, Ib, IIa, IIb, IIIa, IIIb, and IV to VI, VIIa, VIIb, VIIIa, VIIIb and VIIIc as described herein and their tautomers and/or pharmaceutically acceptable salts, compositions, and methods of uses thereof.
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Paragraph 0334
(2015/07/23)
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- The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1)
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Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, suc
- Di Fruscia, Paolo,He, Yuanjun,Koenig, Marcel,Tabrizifard, Sahba,Nieto, Ainhoa,McDonald, Patricia H.,Kamenecka, Theodore M.
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supporting information
p. 3974 - 3978
(2014/10/15)
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- BRADYKININ RECEPTOR ANTAGONISTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to novel compounds, their use in the prevention or treatment of symptoms and disorders associated with the bradykinin B1 pathway and pharmaceutical compositions containing them.
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- Virtual screening and structure-based discovery of indole acylguanidines as potent β-secretase (BACE1) inhibitors
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Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.
- Zou, Yiquan,Li, Li,Chen, Wuyan,Chen, Tiantian,Ma, Lanping,Wang, Xin,Xiong, Bing,Xu, Yechun,Shen, Jingkang
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p. 5706 - 5722
(2013/06/27)
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- Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists
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A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor.
- Wu, Lingyun,Lu, Kai,Packiarajan, Mathivanan,Jubian, Vrej,Chandrasena, Gamini,Wolinsky, Toni C.,Walker, Mary W.
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scheme or table
p. 2167 - 2171
(2012/04/18)
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- SUBSTITUTED AMINO CARBOXYLIC ACIDS
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Disclosed are compounds and pharmaceutically acceptable salts of formula (I): which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-1B (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.
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Page/Page column 188-189
(2008/06/13)
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- Ramoplanin derivatives possessing antibacterial activity
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Novel ramoplanin derivatives are disclosed. These ramoplanin derivatives exhibit antibacterial activity. As the compounds of the subject invention exhibit potent activities against gram positive bacteria, they are useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.
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Page/Page column 52
(2010/11/23)
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- 4-AMINOMETHYL-1-ARYL-CYCLOHEXYLAMINE DERIVATIVES
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The invention concerns 4-aminomethyl-1-aryl-cyclohexylamine derivatives, methods for producing same, medicines containing said compounds and the use of 4-aminomethyl-1-aryl-cyclohexylamine derivatives for producing medicines.
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- Methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis using substituted indolealkanoic acids
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Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds use
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- Design, synthesis, DNA-binding and cytotoxicity evaluation of new potential combilexines
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Combilexines, compounds in which a DNA intercalator is linked to a minor groove binding component, interact with the DNA in a sequence specific manner to yield in most cases compounds with anticancer activity. A series of new compounds closely related to netropsin in which the two components were linked by an amide group was synthesised as potential combilexines. As some of these compounds showed cytotoxic activity in vitro, an attempt was made to rationalise their mechanism of action. The DNA binding characteristics of the carboxamides were evaluated by thermal denaturation experiments and by ethidium bromide displacement assay. Their ability to inhibit the topoisomerase I was also determined. It was concluded that the new compounds were only weak DNA ligands although able in some cases to inhibit topoisomerase I.
- Hotzel, Christian,Marotto, Annalisa,Pindur, Ulf
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p. 367 - 378
(2007/10/03)
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- Compositions containing a substituted indolealkanoic acid and an angiotensin converting enzyme inhibitor
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Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds use
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- IMIDAZOLE WITH ANGIOTENSIN II ANTAGONIST PROPERTIES
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This invention relates to novel substituted imidazole and triazole derivatives which antagonize the binding of angiotensin II to its receptors. The compounds are useful in the treatment of hypertension, heart failure, glaucoma, and hyperaldosteronism. Methods of making the compounds, novel intermediates useful in the preparation of the compounds, pharmaceutical compositions containing the compounds, and methods of using them are also covered.
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- Indanediones-1,3 VIII. Hydroxy-2 indolyl-2 indanediones-1,3, (indolyl-3 methylene)-2 indanediones-1,3 et derives: recherche d'une activite anti-inflammatoire
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1,3-Indandiones VIII. 2-Hydroxy-2-indolyl-1,3-indandiones, 2-(indol-3-ylmethylene indandione and derivatives: search for anti-inflammatory activity.A series of 2-hydroxy-2-indolyl-1,3-indandiones, diversely substituted on the heterocycle were synthetized in order to study their anti-inflammatory activity.Catalytic hydrogenation gave 2,3-dihydroxy-1 indanones 6 and NaBH4 reduction of 3i led to the corresponding indanetriol 7i.Base-catalyzed isomerization of hydroxy-β-diketones 3 furnished 3-indololylcarbonyl phthalides 9.Only compound 3d exhibited a significant inhibition of mouse paw edema.Experimentation in the rat paw edema test confirmed the anti-inflammatory effect of 3d, but it was associated with an anti-coagulant activity. ω-Amino-alkylation of the indole nitrogen of 3d led to loss of anti-inflammatory activity.Introduction of a double bond between the indandione and indole nuclei, leading to 2-(indol-3-ylmethylene)-1,3 indandiones 12, proved ineffective in raising this activity. 2-hydroxy-2-indolyl-1,3-indandiones/ 2,3-dihydroxyindanones/ 1,2,3-indantriols/ 3-indolylcarbonyl-phthalides/ 2-(indol-3-ylmethylene)-1,3-indandiones/ anti-inflammatory activity/ anti-coagulant activity
- Courant, Jacqueline,Leblois, Danielle,Tandon, Manju,Robert-Piessard, Sylvie,le Baut, Guillaume,et al.
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p. 145 - 154
(2007/10/02)
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- Reactivity of a tetrahedral Intermediate in Hydrolysis of N-Acetylpyrrole
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Base hydrolysis of N-acetylpyrrole (1a) involves formation of an anionic tetrahedral intermediate (2a).The equilibrium constant between these two species can be estimated by extrapolation based on the equilibrium constants for hydration of N-trichloroacetyl and N-trifluoroacetylpyrrole and the estimated pKa for deprotonation of the hydrates of these compounds.Inductive effects upon hydration and deprotonation of the hydrates were estimated by analogy with inductive effects upon the equilibrium reactions of chloral and acetaldehyde.The free energies of activation for formation and return of 2a are approximately 16 and 12.5 Kcal mole-1 respectively and for conversion of 2a to products 11 Kcal mole-1 in aqueous 1M OH-.
- Cipiciani, Antonio,Savelli, Gianfranco,Bunton, Clifford A.
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p. 975 - 976
(2007/10/02)
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- ACIDIC PROPERTIES OF N-HETARYLACETIC ACIDS AND INDUCTIVE CONSTANTS OF N-HETARYL SUBSTITUENTS
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The inductive constants of the corresponding heterocyclic fragments were calculated on the basis of data on the pKa values obtained by potentiometric titration of derivatives of indole, carbazole, 3-methylcarbazole, tetrahydrocarbazole, 6-methyltetrahydrocarbazole, and phenothiazine.The ?0R constant of the 9-carbazolyl group was also calculated.The enthalpy and entropy of acidic dissociation were calculated from data on the effect of temperature on the pKa of 9-carbazolylacetic acid.It is shown that the entropy contribution to the free energy of dissociation of 9-carbazolylacetic acid predominates.
- Filippova, T. A.,Sukhoroslova, M. M.,Lopatinskii, V. P.,Filimonov, V. D.
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p. 300 - 303
(2007/10/02)
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- Indole cephalosporin derivatives
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New indole derivatives of cephalosporin compounds have been prepared which are useful as antibiotics.
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