- IMPROVED METHOD FOR PREPARING N-(BENZENESULFONYL)-L-PROLYL- L-O-(1-PYRROLIDINYLCARBONYL)TYROSINE
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The present invention relates to an improved synthetic process for preparing N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine. The present invention is also directed to individual steps in this process and individual intermediates used in
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Page/Page column 33
(2021/06/22)
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- Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95
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Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by 1H,15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.
- Zang, Jie,Ye, Fei,Solbak, Sara M. ?.,H?j, Lars J.,Zhang, Mingjie,Bach, Anders
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supporting information
p. 949 - 954
(2020/12/31)
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- Catalytic Access to Functionalized Allylic gem-Difluorides via Fluorinative Meyer–Schuster-Like Rearrangement
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An unprecedented approach for efficient synthesis of functionalized allylic gem-difluorides via catalytic fluorinative Meyer–Schuster-like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low-cost B–F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem-difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem-difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3-fluorine migration under the assistance of the B–F reagents to give the desired products.
- An, Rui,Li, Huimin,Liao, Lihao,Wu, Jin-Ji,Xu, Yang,Zhao, Xiaodan
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supporting information
p. 11010 - 11019
(2020/05/18)
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- Design, synthesis, molecular docking, antimicrobial, and antioxidant activities of new phenylsulfamoyl carboxylic acids of pharmacological interest
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The research explores the facile synthesis of some new phenylsulfamoyl carboxylic acids, their molecular docking, antimicrobial, and antioxidant activities. The procedure involved the mild reaction of amino acids with benzenesulfonyl chloride in a medium
- Egbujor, Melford C.,Okoro, Uchechukwu C.,Okafor, Sunday
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p. 2118 - 2127
(2019/11/03)
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- New carboxamides bearing benzenesulphonamides: Synthesis, molecular docking and pharmacological properties
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Ten new derivatives of benzenesulphonamide bearing carboxamide functionality were synthesized and investigated for their in vitro antimicrobial, antioxidant and in vivo anti-inflammatory activities. Compound 9d inhibited carrageenan induced rat-paw oedema
- Eze, Florence Uchenna,Okoro, Uchechukwu Chris,Ugwu, David Izuchukwu,Okafor, Sunday N.
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- Synthesis, characterization and in vitro antitrypanosomal activities of new carboxamides bearing quinoline moiety
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The reported toxicities of current antitrypanosomal drugs and the emergence of drug resistant trypanosomes underscore the need for the development of new antitrypanosomal agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide derivatives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new derivatives showed comparable antitrypanosomal activities at IC50 range of 1–6 nM (melarsoprol 5 nM). Compound 11n and 11v are more promising antitrypanosomal agents with IC50 1.0 nM than the rest of the reported derivatives. The novel compounds showed satisfactory predicted physico-chemical properties including oral bioavailability, permeability and transport properties.
- Ugwu, David Izuchukwu,Okoro, Uchechukwu Chris,Mishra, Narendra Kumar
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- Synthesis of proline derived benzenesulfonamides: A potent anti-Trypanosoma brucei gambiense agent
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Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight
- Ugwu, David I.,Okoro, Uchechukwu C.,Mishra, Narendra K.
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supporting information
p. 110 - 116
(2018/05/24)
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- Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies
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Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of t
- Ugwu, David Izuchukwu,Okoro, Uchechukwu Christopher,Ukoha, Pius Onyeoziri,Okafor, Sunday N.,Gupta, Astha
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p. 405 - 415
(2018/03/21)
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- Synthesis, characterization, molecular docking and in?vitro antimalarial properties of new carboxamides bearing sulphonamide
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Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in?vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in?vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08?μM respectively comparable with chloroquine 0.06?μM. Compound 7c was the most potent antioxidant agent with IC50 value of 0.045?mM comparable with 0.34?mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria.
- Ugwu,Okoro,Ukoha,Okafor,Ibezim,Kumar
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p. 349 - 369
(2017/05/04)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and the treatment of certain conditions such as COPD.
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Page/Page column 197
(2013/02/28)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols of formula (I), methods of preparing such compounds, compositio
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Page/Page column 284
(2013/02/27)
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- New chiral aminoamidoximes: Syntheses and investigation of heterocyclic compounds
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New chiral aminoamidoximes were prepared from (L)-proline, (L)-alanine, and (L)-isoleucine by treatment of the corresponding aminonitriles with hydroxylamine in the presence of triethylamine. The intramolecular cyclization with α-bromoacid chlorides and aldehydes was investigated to give new 1,2,4-oxadiazin-6-ones and 1,2,4-oxadiazoles, respectively. These compounds were likely to undergo an intermolecular cyclization through oxygen and nitrogen. However, intramolecular cyclization through two nitrogens did not occur even after changing reaction conditions. Taylor & Francis Group, LLC.
- Tka, Najeh,Hassine, Bechir Ben
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scheme or table
p. 828 - 835
(2012/02/03)
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- Synthesis and structure-activity relationships of o-sulfonamido- arylhydrazides as inhibitors of LL-diaminopimelate aminotransferase (LL-DAP-AT)
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Recently, ll-diaminopimelate aminotransferase (ll-DAP-AT), a pyridoxal-5′-phosphate (PLP)-dependent enzyme, was reported to catalyze a key step in the biosynthesis of l-lysine in plants and Chlamydia. Previous screening of a 29201-compound library against
- Fan, Chenguang,Vederas, John C.
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supporting information; experimental part
p. 5815 - 5819
(2012/08/28)
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- New Pharmaceutical Compounds
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Compounds of formula I, wherein A and R1-R7, are as defined in the claims, exhibit TRPA1 activity and are thus useful as TRPA1 modulators.
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Page/Page column 11
(2012/12/13)
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- PHENYL- SULFONYL DERIVATIVES AS MEDIATORS OF TRPA1 RECEPTOR ACTIVITY FOR THE TREATMENT OF PAIN
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Compounds of formula I, wherein A and R1-R7, are as defined in the claims, exhibit TRPA1 activity and useful as TRPA1 modulators.
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Page/Page column 20-21
(2012/12/13)
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- Design, synthesis and in vitro biochemical activity of novel amino acid sulfonohydrazide inhibitors of MurC
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Mur ligases are essential enzymes involved in the cytoplasmic steps of peptidoglycan synthesis which remain attractive, yet unexploited targets. In order to develop new antibacterial agents, we have designed a series of new MurC and MurD inhibitors bearin
- Frlan, Rok,Kovas, Andreja,Blanot, Didier,Gobec, Stanislav,Pecar, Slavko,Obreza, Ales
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scheme or table
p. 295 - 310
(2012/04/23)
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- Small molecule antagonists of the CC chemokine receptor 4 (CCR4)
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The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer
- Burdi, Douglas F.,Chi, Shannon,Mattia, Karen,Harrington, Celeste,Shi, Zhan,Chen, Shaowu,Jacutin-Porte, Swanee,Bennett, Robert,Carson, Kenneth,Yin, Wei,Kansra, Vikram,Gonzalo, Jose-Angel,Coyle, Anthony,Jaffee, Bruce,Ocain, Timothy,Hodge, Marty,LaRosa, Gregory,Harriman, Geraldine
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p. 3141 - 3145
(2008/09/21)
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- Synthesis, calpain inhibitory activity, and cytotoxicity of P 2-substituted proline and thiaproline peptidyl aldehydes and peptidyl α-ketoamides
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Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the μ-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl α-ketoamides with N-sub
- Korukonda, Rajani,Guan, Na,Dalton, James T.,Liu, Jiuyu,Donkor, Isaac O.
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p. 5282 - 5290
(2007/10/03)
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- Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
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The present invention relates to urotensin II receptor antagonists, CCR-9 antagonists, pharmaceutical compositions containing them and their use.
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- An assessment of the mechanistic differences between two integrin α4β1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis
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Integrin α4β1 plays an important role in inflammatory processes by regulating the migration of lymphocytes into inflamed tissues. Here we evaluated the biochemical, pharmacological, and pharmacodynamic properties and efficacy in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, of two types of α4β1 inhibitors, the anti-rat α4 monoclonal antibody TA-2 and the small molecule inhibitor BIO5192 [2(S)-{[1(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino} 4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}amino)- pentanoylamino]-butyric acid]. TA-2 has been extensively studied in rats and provides a benchmark for assessing function. BIO5192 is a highly selective and potent (KD of 4β1. Dosing regimens were identified for both inhibitors, which provided full receptor occupancy during the duration of the study. Both inhibitors induced leukocytosis, an effect that was used as a pharmacodynamic marker of activity, and both were efficacious in the EAE model. Treatment with TA-2 caused a decrease in α4 integrin expression on the cell surface, which resulted from internalization of α4 integrin/TA-2 complexes. In contrast, BIO5192 did not modulate cell surface α4β1. Our results with BIO5192 indicate that α4β7 does not play a role in this model and that blockade of α4β1/ligand interactions without down-modulation is sufficient for efficacy in rat EAE. BIO5192 is highly selective and binds with high affinity to α4β1 from four of four species tested. These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of α4β1 integrin, will be a valuable reagent for assessing α4β1 biology and may provide a new therapeutic for treatment of human inflammatory diseases.
- Leone,Giza,Gill,Dolinski,Yang,Perper,Scott,Lee,Cornebise,Wortham,Nickerson-Nutter,Chen,Lepage,Spell,Whalley,Petter,Adams,Lobb,Pepinsky
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p. 1150 - 1162
(2007/10/03)
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- Preparation of both enantiomers of 1-allyl-1,2,3,4-tetrahydro-β-carboline using allyltin reagents and a chiral auxiliary derived from L-proline
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β-Carboline, which had an acyl group derived from L-proline at the 9-position, reacted with allyltributyltin and 2,2,2-trichloroethyl chloroformate to afford an 1-allyl-1,2-dihydro-β-carboline derivative in a diastereoselective manner. The chiral acyl group at N-9 was readily eliminated by aqueous alkali to give a corresponding carboxylic acid. The formed 1-allyl-1,2-dihydro-β-carboline was transformed via two reduction steps to 1-allyl-1,2,3,4-tetrahydro-β-carboline in high ee. When the allylation was carried out using tetraallyltin instead of allyltributyltin, the stereoselectivity was reversed, and the antipode of the allyl adduct was obtained in high yield and ee in the presence of tin(IV) tetraiodide. Thus, it was found that both enantiomers of 1-allyl-β-carboline were obtained in good enantioselectivities by the use of the same chiral auxiliary.
- Itoh, Takashi,Matsuya, Y?ji,Enomoto, Yasuko,Ohsawa, Akio
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p. 7277 - 7289
(2007/10/03)
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- Stereoselective addition of methyl acrylate to α-amino aldehydes
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Variously N-protected α-aminoaldehydes exhibit reasonable diastereoselectivity in the Baylis-Hillman coupling with methyl acrylate to provide either primarily syn or anti α-methylene-β-hydroxy-γ-amino esters.
- Manickum,Roos
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p. 2269 - 2274
(2007/10/02)
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- ASYMMETRIC SYNTHESIS OF (S)-CAMPTOTHECIN
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The title compound was synthesized via a novel diastereoselective ethylation process from indolizine derivative 5a bearing N-tosyl-(R)-proline.
- Ejima, Akio,Terasawa, Hirofumi,Sugimori, Masamichi,Tagawa, Hiroaki
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p. 2639 - 2640
(2007/10/02)
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- α-Amino Acids as Chiral Educts for Asymmetric Products. The Synthesis of α'-Amino-α,β-ynones
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α-Amino acid isoxazolidides have been developed as educts for the preparation of optically pure α'-amino-α,β-ynones.The α-amino acids were first N-protected as their ethoxycarbonyl, tert-butoxycarbonyl, or phenylsulfonyl derivatives.The isoxazolidides then were formed by the simple, high yield acylation of isoxazolidine by in situ generated α-amino acid isobutyl carbonic anhydrides.Individual isoxazolidides of L-α-N-substituted alanine, phenylalanine, and methionine, when treated with lithium acetylide, lithium (trimethylsilyl)acetylide, or 1-hexynyllithium, gave high yields of the corresponding optically pure α,β-acetylenic ketones.
- Cupps, Thomas L.,Boutin, Raymond H.,Rapoport, Henry
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p. 3972 - 3979
(2007/10/02)
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- Synthesis and Liquid Chromatographic Evalution of Some Chiral Derivatizing Agents for Resolution of Amine Enantiomers
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A series of 1-prolyl chlorides were synthesized and evaluated as chiral derivatizing agents for the liquid chromatographic analysis of enantiomeric amines.The diastereomeric 1-prolinamides showed st
- Clark, C. Randall,Berksdale, Jeffrey M.
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p. 958 - 962
(2007/10/02)
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- alpha -AMINO ACIDS AS CHIRAL EDUCTS FOR ASYMMETRIC PRODUCTS. A GENERAL SYNTHESIS OF D- alpha -AMINO ACIDS FROM L-SERINE.
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A short and chirally efficient synthesis of four D- alpha -amino acids is described with L-serine as the chiral educt. The key C-C bond-forming reactions are the aminoacylations of organometallics with the lithium salt of N-(phenylsulfonyl)-L-serine (2) to give optically pure N-blocked alpha -amino ketones. Reduction of the carbonyl group to carbinol or methylene followed by oxidation of the hydroxymethyl to carboxyl gives the N-blocked D-amino acids. The examples investigated (norleucine, alpha -aminopimelic acid, DOPA, and allothreonine) demonstrate the broad applicability of the method.
- Maurer,Takahata,Rapoport
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p. 1095 - 1098
(2007/10/02)
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