- Design, synthesis and biological evaluation of HIV-1 protease inhibitors with morpholine derivatives as P2 ligands in combination with cyclopropyl as P1′ ligand
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A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1′ ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.
- Dong, Biao,Dou, Yue,Wang, Ju-Xian,Wang, Yu-Cheng,Zhang, Fan,Zhang, Guo-Ning,Zhu, Mei
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Read Online
- Photolysis of C60 with cyclic amino acids: Preparation of dihydrofullerenes by decarboxylation
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Photolysis of C60 with piperidinoacetic acid and morpholinoacetic acid results in the decarboxylation of the acids and formation of the 1,2-dihydrofullerenes C60(H)[CH2N(CH2)5] 1, C60(H)[CH2N(CH2CH2)2O] 2. Under the same conditions the reactions with the methyl esters of the two cyclic amino acids give the fullerropyrrolidine derivatives C60[CH(CH2)4NCH-COOCH3] 3, and C60[CH(CH2OCH2)NCHCOOCH3] 4.
- Zhang, Wen,Su, Yang,Gan, Liangbing,Jiang, Jianfeng,Huang, Chunhui
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Read Online
- Nitrogen-containing cyclic compounds as iminium ion sources for selected reaction monitoring detection of derivatized analytes
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Liquid chromatography–tandem mass spectrometry is one of the most sensitive tools for determination of trace amounts of analytes in metabolomics and proteomics. The highest sensitivity is achieved in selected reaction monitoring detection, which involves fragmentation of the molecular ion between two levels of mass selection. However, fragmentation of some compounds is complicated. Detection sensitivity of such analytes may be increased by derivatizing them with a specific moiety fragmentation of which results in product ion of high abundance. In this work, we reveal the influence of iminium ions' structures on their stability by comparing six nitrogen-containing cyclic compounds as derivatization reagents for tandem mass spectrometric analysis of amino group-containing analyte. Commercially available starting materials (piperidine, 2,6-dimethylpiperidine, 1-methylpiperazine, morpholine, pyrrolidine and 1-cyanomethyl-3-methylimidazolium ionic liquid) were used for the synthesis of corresponding carboxylic acids which were further used for derivatization of the model analyte tryptamine. Liquid chromatographic–mass spectrometric analysis of differently derivatized tryptamine was performed for the evaluation of release and stability of corresponding iminium ions under collision-induced dissociation conditions. As a result, morpholine moiety was shown being the most promising iminium ion source among tested compounds. Possible sub-fragmentation pathways of investigated iminium ions were discussed, and the structures of secondary product ions were proposed.
- ?ilionis, Andrius
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supporting information
p. 25 - 35
(2019/09/03)
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- Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants
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Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme Ki of 0.092 nM and 0.21 nM, as well as antiviral IC50 values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94percent and 91percent, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.
- Cen, Shan,Dong, Biao,Dou, Yue,Ma, Ling,Wang, Juxian,Wang, Yucheng,Zhang, Fan,Zhang, Guoning,Zhou, Jinming,Zhu, Mei
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supporting information
p. 1196 - 1204
(2020/07/04)
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- Reagent-free continuous thermal tert-butyl ester deprotection
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Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120–240 °C and 15–40 min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.
- Cole, Kevin P.,Ryan, Sarah J.,Groh, Jennifer McClary,Miller, Richard D.
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p. 6209 - 6217
(2017/09/30)
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- Development of a series of bis-triazoles as G-quadruplex ligands
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Maintenance of telomeres-specialized complexes that protect the ends of chromosomes-is provided by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types. Telomeric ends of chromosomes consist of noncoding repeat sequences of guanine-rich DNA. These G-rich ends can fold into structures called G-quadruplexes. Stabilization of G-quadruplexes by small binding molecules called G4 ligands can prevent telomerase enzyme from maintaining telomere integrity in cancer cells. G-quadruplexes can exist in other parts of the genome too, especially within promoter sequences of oncogenes, and also be interesting drug targets. Here, we describe the development of a new series of novel bis-triazoles, designed to stabilize G-quadruplex structures selectively as G4 ligands. FRET assays showed two compounds to be moderately effective G4 binders, with particular affinity for the quadruplex formed by the Hsp90a promoter sequence, and good selectivity for G-quadruplex DNA vs. duplex DNA. However, CD spectroscopy failed to provide any information about the folding topology of the human telomeric G-quadruplex resulting from its interaction with one of the ligands. All the new ligands showed potent cell growth inhibitory properties against human colon and pancreatic cancer cell lines, as evidenced by the MTT assay; notably, they were more potent against cancer cells than in fetal lung fibroblasts. Docking studies were performed to rationalize the affinity of these ligands for binding to the telomeric parallel G-quadruplex DNA.
- Saleh, Maysaa M.,Laughton, Charles A.,Bradshaw, Tracey D.,Moody, Christopher J.
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p. 47297 - 47308
(2017/10/19)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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Paragraph 0145
(2015/02/18)
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- ISOQUINOLINE AND NAPHTHYRIDINE DERIVATIVES
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The invention provides novel compounds having the general formula(I) wherein A, R1 and R2 are as described herein, compositions including the compounds and use of the compounds for inhibiting angiogenesis by inhibition of MAP4K4.
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Page/Page column 97
(2013/08/15)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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Page/Page column 40
(2013/04/25)
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- MAXI-K CHANNEL BLOCKERS AND METHODS OF USE
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This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.
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Page/Page column 70
(2009/05/28)
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- CHEMOKINE RECEPTOR BINDING COMPOUNDS
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The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR5. Thesd compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
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(2008/06/13)
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- NK1 and NK3 antagonists
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The invention is to a compound exhibiting neurokinin inhibitory properties, a pharmaceutical composition comprising same and a method of treatment for neurokinin-mediated conditions.
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Page/Page column 27
(2010/02/14)
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- Compositions and kits pertaining to analyte determination
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This invention pertains to methods, mixtures, kits and/or compositions for the determination of analytes by mass analysis using unique labeling reagents or sets of unique labeling reagents. The labeling reagents can be isomeric or isobaric and can be used to produce mixtures suitable for multiplex analysis of the labeled analytes.
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- Insertion of an aspartic acid moiety into cyclic pseudopeptides: Synthesis and biological characterization of potent antagonists for the human tachykinin NK-2 receptor
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A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED50 = 0.27 nmol/kg and 0.15 nmol/kg, respectively).
- Fedi, Valentina,Altamura, Maria,Balacco, Giuseppe,Canfarini, Franca,Criscuoli, Marco,Giannotti, Danilo,Giolitti, Alessandro,Giuliani, Sandro,Guidi, Antonio,Harmat, Nicholas J. S.,Nannicini, Rossano,Pasqui, Franco,Patacchini, Riccardo,Perrotta, Enzo,Tramontana, Manuela,Triolo, Antonio,Maggi, Carlo Alberto
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p. 6935 - 6947
(2007/10/03)
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- HETEROCYCLIC MODULATORS OF NUCLEAR RECEPTORS
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Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of farnesoid X receptor (FXR), liver X receptor (LXR) and/or orphan nuclear receptors. In certain embodiments, the compounds are thiazolidinone derivatives.
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- Heterocyclic compounds as inhibitors of rotomase enzymes
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Compounds of the formula: wherein R1, Y, W, A and R2are as defined above are inhibitors of rotamase enzymes in particular FKBP-12 and FKBP-52. The compounds therefore moderate neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases and nerve damage.
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- Heterocycle derivatives and drugs
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The object of the invention is to provide an excellent compound as a drug. The invention relates to a heterocyclic compound shown by the following formula: A-B-D-E [1] wherein A is heteroaryl or its oxide; B is ethenylene; D is optionally substituted phenylene; and E is a group of the formula: ?wherein G is optionally substituted phenyl; and R is heteroaryl or heteroarylmethyl, or a group of the formula: ?wherein n is an integer of 1 to 5; R5 and R6 are same or different and are independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 taken together with the adjacent nitrogen atom may form 5- to 7-membered cyclic amino group for —NR5R6 or a salt thereof.
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- Dexanabinol derivatives and their use as neuroprotective pharmaceutical compositions
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PCT No. PCT/US95/01470 Sec. 371 Date Sep. 28, 1998 Sec. 102(e) Date Sep. 28, 1998 PCT Filed Feb. 6, 1995 PCT Pub. No. WO95/20958 PCT Pub. Date Aug. 10, 1995The present invention relates to pharmaceutical compositions for preventing or alleviating neurotoxicity. Said pharmaceutical compositions comprise as their active ingredient the stereospecific (+) enantiomers, having (3S,4S) configuration, of DELTA 6-tetrahydrocannabinol (THC) type compounds of general formula (I), as defined hereinbelow.
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- Fast ester cleavage of sterically hindered α- and β-aminoesters under non-aqueous conditions. Application to the kinetic resolution of aziridine esters
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Various protected α- and β-aminoesters undergo fast ester cleavage by treatment with t-BuOK in THF. The accelerating effect of a neighboring chelating group was used for the efficient kinetic resolution of non-racemic aziridine esters. (C) 2000 elsevier Science Ltd.
- Alezra, Valérie,Bouchet, Céline,Micouin, Laurent,Bonin, Martine,Husson, Henri-Philippe
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p. 655 - 658
(2007/10/03)
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- Synthesis and in vitro evaluation of novel morpholinyl- and methylpiperazinylacyloxyalkyl prodrugs of 2-(6-methoxy,2-naphthyl)propionic acid (naproxen) for topical drug delivery
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Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c- f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1- piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1- 26 min) to naproxen in human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4-and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-ionized under neutral and slightly acidic conditions, and thus, a desirable combination is achieved in terms of aqueous solubility and lipophilicity. Moreover, the resulting combination of biphasic solubility and fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave improved topical delivery of naproxen.
- Rautio, Jarkko,Nevalainen, Tapio,Taipale, Hannu,Veps?l?inen, Jouko,Gynther, Jukka,Laine, Krista,J?rvinen, Tomi
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p. 1489 - 1494
(2007/10/03)
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- Method for lowering total serum cholesterol and treating hypercholesterolemia with aminoacetylmercapto derivatives
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The present invention relates to the use of certain aminoacetylmercapto derivatives in treating patients suffering from hypercholesterolemia.
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- AMINOACETYLMERCAPTO DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
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The present invention relates to novel aminoacetylmercapto derivatives useful as inhibitors of enkephalinase and ACE.
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- Symmetry-Based Inhibitors of HIV Protease. Structure-Activity Studies of Acylated 2,4-Diamino-1,5-diphenyl-3-hydroxypentane and 2,5-Diamino-1,6-diphenylhexane-3,4-diol
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The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described.Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed.Aqueous solubility was enhanced >1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro.Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors.The oral bioavailability of inhibitor 19 in rats was 19percent; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro.Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.
- Kempf, Dale J.,Codacovi, Lynnmarie,Wang, Xiu Chun,Kohlbrenner, William E.,Wideburg, Norman E.,et al.
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p. 320 - 330
(2007/10/02)
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- Diphenylboron Chelates of α-(Dialkylamino)carboxylic Acids and their N-Oxides
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α-(Dialkylamino)carboxylic acids and their N-oxides react with oxybis(diphenylborane) or similar diphenylborane derivatives to give five- or six-membered diphenylboron chelate rings, respectively, the structure of which is supported by spectroscopic evidence.
- Kliegel, Wolfgang,Graumann, Juergen
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p. 950 - 961
(2007/10/02)
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