- A concise synthetic route to the stereotetrad core of the briarane diterpenoids
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A concise synthesis (under 10 steps) of the stereotetrad core of the briarane diterpenoids is reported. This approach harnesses the unique reactivity of salicylate ester derived 2,5-cyclohexadienones to quickly build complexity. In particular, a highly diastereoselective acetylide conjugate addition/β-ketoester alkylation sequence was used to set the relative configuration of the C1 (quaternary) and C10 (tertiary) vicinal stereocenters. The sterochemical outcome of the β-ketoester alkylation appears to be governed by torsional steering in the transition state.
- Moon, Nicholas G.,Harned, Andrew M.
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Read Online
- Synthesis and biological evaluation of novel 5,6,7-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents
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5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC50 values of 10.26 ± 6.94 μM and 17.17 ± 3.03 μM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f, as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies.
- Deng, Xiangping,Feng, Wanshi,Lei, Xiaoyong,Liu, Renbo,Peng, Yijiao,Tang, Guotao,Xie, Zhizhong,Xiong, Runde,Zheng, Xing,Zou, Yang
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- Design, synthesis, and preliminary biological evaluation of 3′,4′,5′-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents
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According to the pharmacophore combination principle, a set of new 3′,4′,5′-trimethoxy flavonoid salicylate derivatives were designed, synthesized, and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment with compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while it had no effect on their cell cycle. The WB analysis suggested that HIF-1α, tubulin, HK-2, and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v, which was explained by analyzing the crystal structure of compound 10v complexed with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation.
- Deng, Xiangping,Liu, Renbo,Li, Junjian,Li, Zhongli,Liu, Juan,Xiong, Runde,Lei, Xiaoyong,Zheng, Xing,Xie, Zhizhong,Tang, Guotao
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p. 1874 - 1884
(2019/01/28)
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- Vitamin Catalysis: Direct, Photocatalytic Synthesis of Benzocoumarins via (-)-Riboflavin-Mediated Electron Transfer
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An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (-)-riboflavin (vitamin B2) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis.
- Morack, Tobias,Metternich, Jan B.,Gilmour, Ryan
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supporting information
p. 1316 - 1319
(2018/03/09)
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- Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid
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Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
- Krogsgaard-Larsen, Niels,Delgar, Claudia G.,Koch, Karina,Brown, Patricia M. G. E.,M?ller, Charlotte,Han, Liwei,Huynh, Tri H. V.,Hansen, Stinne W.,Nielsen, Birgitte,Bowie, Derek,Pickering, Darryl S.,Kastrup, Jette Sandholm,Frydenvang, Karla,Bunch, Lennart
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p. 441 - 457
(2017/04/26)
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- Intramolecular C-H activation through gold(I)-catalyzed reaction of iodoalkynes
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The cycloisomerization reaction of 1-(iodoethynyl)-2-(1-methoxyalkyl)arenes and related 2-alkyl-substituted derivatives gives the corresponding 3-iodo-1-substituted-1H-indene under the catalytic influence of IPrAuNTf2 [IPr = 1,3-bis(2,6-diisopropyl)phenylimidazol-2-ylidene; NTf2 = bis(trifluoromethanesulfonyl)imidate]. The reaction takes place in 1,2-dichloroethane at 80°C, and the addition of ttbp (2,4,6-tritert-butylpyrimidine) is beneficial to accomplish this new transformation in high yield. The overall reaction implies initial assembly of an intermediate gold vinylidene upon alkyne activation by gold(I) and a 1,2-iodine-shift. Deuterium labeling and crossover experiments, the magnitude of the recorded kinetic primary isotopic effect, and the results obtained from the reaction of selected stereochemical probes strongly provide support for concerted insertion of the benzylic C-H bond into gold vinylidene as the step responsible for the formation of the new carbon-carbon bond.
- Morn-Poladura, Pablo,Rubio, Eduardo,Gonzlez, Jos M.
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supporting information
p. 3052 - 3055
(2015/04/14)
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- HEPATITIS B CORE PROTEIN ALLOSTERIC MODULATORS
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ABSTRACT The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.
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Paragraph 000194
(2015/10/05)
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- Discovery and structure-activity relationship of novel 2,3- dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2 h)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 Inhibitors
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Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
- Patel, Maulik R.,Bhatt, Aaditya,Steffen, Jamin D.,Chergui, Adel,Murai, Junko,Pommier, Yves,Pascal, John M.,Trombetta, Louis D.,Fronczek, Frank R.,Talele, Tanaji T.
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p. 5579 - 5601
(2014/08/05)
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- Palladium-catalyzed intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides
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Give me a ring? An efficient approach has been developed for the intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides catalyzed by palladium (see scheme). From a synthetic viewpoint, this method is highly attractive because the catalyst loading is low, the optimized reaction conditions are mild, and the substrate scope is broad. Copyright
- Shen, Zengming,Ni, Zhenjie,Mo, Song,Wang, Jing,Zhu, Yamin
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supporting information; experimental part
p. 4859 - 4865
(2012/06/04)
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- Synthesis of new tripodal hydroxybenzoic esters and their reaction with tris-(2-aminoethyl)amine under high pressure conditions
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The new simple method of synthesis of tripodal esters, building blocks for monomacrocyclic pendant macrocycles and bicyclic cryptands is reported. Six new tripodal esters, derivatives of hydroxybenzoic acids were prepared and characterized, and their reaction with tris(2-aminoethyl)amine carried under high pressure conditions was studied using Electrospray Ion Mass Spectrometry.
- Ceborska, Magdalena,Jurczak, Janusz
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body text
p. 114 - 117
(2012/07/28)
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- Synthesis and pharmacological evaluation of fluorine-containing D 3 dopamine receptor ligands
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A series of fluorine-containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized, and their affinities for human dopamine D2, D3, and D4 receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e, and 21e, which bind with high affinity at D3 (K i = 0.17-5 nM) and moderate to high selectivity for D3 vs D2 receptors (ranging from ～25- to 163-fold). These compounds were also evaluated for intrinsic activity at D2 and D3 receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D2 vs D3 receptors. These compounds may be useful for behavioral pharmacology studies on the role of D2-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D3 receptor (Ki = 0.17 nM for D3, 163-fold selectivity for D3 vs D2 receptors), represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D3 receptor expression.
- Tu, Zhude,Li, Shihong,Cui, Jinquan,Xu, Jinbin,Taylor, Michelle,Ho, David,Luedtke, Robert R.,MacH, Robert H.
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scheme or table
p. 1555 - 1564
(2011/06/19)
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- HETEROCYCLIC DERIVATIVE HAVING INHIBITORY ACTIVITY ON TYPE-I 11 -HYDROXYSTEROID DEHYDROGENASE
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Disclosed is a compound which is useful as an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. A compound represented by the formula: its pharmaceutically acceptable salt, or a solvate thereof, wherein X is O or S, a broken line and a wavy line represent the presence or the absence of a bond, (i) when a broken line represents the presence of a bond, a wavy line represents the absence of a bond, R2 and R3 are each independently hydrogen, halogen, cyano, hydroxy, carboxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or the like, (ii) when a broken line represents the absence of a bond, a wavy line represents the presence of a bond, R1 and R4 are each independently hydrogen, halogen or the like, R2 and R3 are each independently hydrogen, halogen, cyano, hydroxy, carboxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or the like, and R5 and R6 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or the like.
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Page/Page column 48
(2010/08/07)
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- Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1′ pocket and their quantitative structure-activity relationship (QSAR) study
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A series of coumarin based TACE inhibitors were designed to bind in S1′ pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1′ pocket and the TACE inhibitory activity well.
- Yang, Jee Sun,Chun, Kwangwoo,Park, Jung Eun,Cho, Misun,Seo, Jeongjea,Song, Doona,Yoon, Hongchul,Park, Chun-Ho,Joe, Bo-Young,Choi, Jong-Hee,Kim, Myung-Hwa,Han, Gyoonhee
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experimental part
p. 8618 - 8629
(2011/02/25)
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- Synthesis, structural investigations, hydrogen-deuterium exchange studies, and molecular modeling of conformationally stablilized aromatic oligoamides
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Biasing the conformational preferences of aromatic oligoamides by internally placing intramolecular hydrogen bonds has led to a series of stably folded molecular strands. This article presents the results from extensive solid-state, solution, and computational studies on these folding oligomers. Depending on its backbone length, an oligoamide adopts a crescent or helical conformation. Surprisingly, despite the highly repetitive nature of the backbone, the internally placed, otherwise very similar intramolecular hydrogen bonds showed significantly different stabilities as demonstrated by hydrogen-deuterium exchange data. It was also observed that the hydrogen-bonding strength can be tuned by adjusting the substituents attached to the exterior of the aromatic backbones. Examining the amide hydrogen-deuterium exchange rates of trimers revealed that a six-membered hydrogen bond nearing the ester end is the weakest among all the four intramolecular hydrogen bonds of a molecule. This observation was verified by ab initio quantum mechanical calculations at the level of B3LYP/6-31G. Such a "weak point" creates the "battle of the bulge" where backbone twisting is centered, which is consistently observed in the solid-state structures of the four trimer molecules studied. In the solid state, the oligomers assemble into interesting one-dimensional structures. A pronounced columnar packing of short oligomers (i.e., dimers, trimers, and tetramer) and channel-like, potentially ion-conducting stacks of longer oligomers (i.e., tetramer, pentamer, and hexamer) were observed.
- Yan, Yan,Qin, Bo,Ren, Changliang,Yip, Yeow Kwan,Ye, Ruijuan,Zeng, Huaqiang,Chen, Xiuying,Su, Haibin,Zhang, Dawei
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supporting information; experimental part
p. 5869 - 5879
(2010/07/13)
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- Helical organization in foldable aromatic oligoamides by a continuous hydrogen-bonding network
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Introduction of a continuous internal hydrogen-bonding network suppressed the conformational flexibility of a series of oligoaromatic foldamers with a lengthened backbone. The helical ordering over up to six aromatic repeating units was established in solution by a 2D NOESY study and in the solid state by an X-ray diffraction method. Computational molecular modeling further corroborates the experimentally observed helical propagation in this class of foldable molecular strands.
- Yan, Yan,Qin, Bo,Shu, Yingying,Chen, Xiuying,Yip, Yeow Kwan,Zhang, Dawei,Su, Haibin,Zeng, Huaqiang
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supporting information; experimental part
p. 1201 - 1204
(2009/08/07)
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- Enzyme-catalysed synthesis and reactions of benzene oxide/oxepine derivatives of methyl benzoates
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A series of twelve benzoate esters was metabolised, by species of the Phellinus genus of wood-rotting fungi, to yield the corresponding benzyl alcohol derivatives and eight salicylates. The isolation of a stable oxepine metabolite, from methyl benzoate, allied to evidence of the migration and retention of a carbomethoxy group (the NIH Shift), during enzyme-catalysed ortho-hydroxylation of alkyl benzoates to form salicylates, is consistent with a mechanism involving an initial arene epoxidation step. This mechanism was confirmed by the isolation of a remarkably stable, optically active, substituted benzene oxide metabolite of methyl 2-(trifluoromethyl)benzoate, which slowly converted into the racemic form. The arene oxide was found to undergo a cycloaddition reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to yield a crystalline cycloadduct whose structure and racemic nature was established by X-ray crystallography. The metabolite was also found to undergo some novel benzene oxide reactions, including epoxidation to give an anti-diepoxide, base-catalysed hydrolysis to form a trans-dihydrodiol and acid-catalysed aromatisation to yield a salicylate derivative via the NIH Shift of a carbomethoxy group. This journal is The Royal Society of Chemistry.
- Boyd, Derek R.,Sharma, Narain D.,Harrison, John S.,Malone, John. F.,McRoberts, W. Colin,Hamilton, John T. G.,Harper, David B.
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experimental part
p. 1251 - 1259
(2008/10/09)
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- Studies on enzyme-cleavable dialkoxymethyl-cycloSaligenyl-2′, 3′-dideoxy-2′,3′-didehydrothymidine monophosphates
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Recently we reported on conceptually new enzymatically activated cycloSal-pronucleotides. Now, we developed this concept further with new compounds of this type. The basic idea is fast intracellular cleavage of a functionalized group at the cycloSal residue that results in a rapid delivery of the nucleotide and thus an intracellular enrichment of the nucleotide. The introduction of a higher alkylated acylal group, the di-iso-butyryloxymethyl group, to the aromatic ring led to the expected higher stability of these prodrugs against enzymatic cleavage but also entailed surprisingly a decrease in hydrolysis stabilities and solubility problems. For some compounds, a separation of the two diastereomeric forms (RP or SP) was achieved. By X-ray structure analysis, the absolute configuration at the P-atom was assigned. For all separated diastereomers the (SP) form showed better antiviral activity than the (RP) form.
- Gisch, Nicolas,Balzarini, Jan,Meier, Chris
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experimental part
p. 6752 - 6760
(2009/11/30)
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- Derivatives of 1,4-bis(3-hydroxycarbonyl-4-hydroxyl)styrylbenzene as PTP1B inhibitors with hypoglycemic activity
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Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC50 value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.
- Shrestha, Suja,Bhattarai, Bharat Raj,Kafle, Bhooshan,Lee, Keun-Hyeung,Cho, Hyeongjin
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p. 8643 - 8652
(2008/12/23)
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- The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex
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The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1′/S2′ pocket.
- Kohrt, Jeffrey T.,Filipski, Kevin J.,Cody, Wayne L.,Cai, Cuiman,Dudley, Danette A.,Van Huis, Chad A.,Willardsen, J. Adam,Rapundalo, Stephen T.,Saiya-Cork, Kamlai,Leadley, Robert J.,Narasimhan, Lakshmi,Zhang, Erli,Whitlow, Marc,Adler, Marc,McLean, Kirk,Chou, Yuo-Ling,McKnight, Cecile,Arnaiz, Damian O.,Shaw, Kenneth J.,Light, David R.,Edmunds, Jeremy J.
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p. 4752 - 4756
(2007/10/03)
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- Hydrogen-bonding-induced oligoanthranilamide foldamers. Synthesis, characterization, and complexation for aliphatic ammonium ions
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The self-assembly of a novel series of intramolecular hydrogen bonding-driven foldamers have been described. Five linear aromatic amide oligomers 1-5, which bear two to six repeating benzoyl amide subunits, respectively, have been prepared by continuous amide-coupling reactions. The existence of three-centered hydrogen bonds in the oligomers and consequently, the folding conformation of the oligomers in the solid state and solution have been proved by the X-ray analysis (for 2) and the 1H NMR and IR experiments. Molecular modeling reveals a planar and rigid conformation for the oligomers and a cavity of 0.86 nm in diameter for 6-mer 5. Fluorescent and 1H NMR experiments have demonstrated that the new aromatic oligo-amide foldamers can bind primary and secondary alkyl ammonium ions in chloroform and the associated binding constants have been determined. It is revealed that 5-mer 4 exhibits the largest binding ability. A face-to-face binding mode has been proposed for the complexes.
- Yi, Hui-Ping,Li, Chuang,Hou, Jun-Li,Jiang, Xi-Kui,Li, Zhan-Ting
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p. 7974 - 7980
(2007/10/03)
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- NOVEL BENSOPHENONE DERIVATIVES OR SALTS THEREOF
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A benzophenone derivative represented by the following formula: whereinR1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl;R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, ???or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.
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Page 123-124
(2010/02/07)
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- Novel indanylidene compounds
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Novel indanylidene compounds can be used as UV-A filters in cosmetic compositions for protecting skin and hair and for technical applications.
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- Method for preparing scenting compositions and scented products, and resulting products
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The present invention relates to a process for the production of perfuming compositions, to perfumed products, and to products obtained therefrom. More specifically, the present invention concerns a process for the production of perfuming compositions, perfumed products and substances for perfumery characterized in that they comprise, as an active ingredient with an influence on the scent, an effective quantity of an alkylsalicylic acid ester.
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- Solid-phase synthesis of new saphenamycin analogues with antimicrobial activity
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An array of 12 new saphenamycin analogues modified at the benzoate moiety was synthesized on solid support. Synthesis commenced with a chemoselective anchoring of saphenic acid through the carboxyl group to a 2-chlorotrityl functionalized polystyrene resin. The secondary alcohol was acylated in parallel with a series of differently substituted benzoic acid derivatives. Treatment with TFA-CH2Cl2 (5:995) released the expected saphenamycin analogues into solution. These new analogues were purified, characterized and screened for antimicrobial activity against Bacillus subtilis and Proteus mirabilis. Eight analogues exhibited MIC values against B. subtilis ranging from 0.07 to 3.93 μg/mL, comparable to the activities of previously reported saphenamycin analogues.
- Laursen, Jane B.,De Visser, Peter C.,Nielsen, Henrik K.,Jensen, Knud J.,Nielsen, John
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p. 171 - 175
(2007/10/03)
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- Pyrimidin derivatives
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The invention relates to new pharmaceutically active compounds which are are P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists, compositions containing them and processes for their preparation.
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- Triaromatic compounds and pharmaceutical/cosmetic compositions comprised thereof
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Novel pharmaceutically/cosmetically-active triaromatic compounds have the structural formula (I): and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular, bone and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.
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- Zatosetron, a Potent, Selective, and Long-Acting 5HT3 Receptor Antagonist: Synthesis and Structure-Activity Relationships
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Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin.Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse.Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists.Simple benzoyl derivatives of tropine and 3α-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats.Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity.The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclooct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate).The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR.Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50=0.86 μg/kg iv).Low oral doses of zatosetron (30 μg/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats.Moreover, this compound did not produce hemodynamic effects after iv administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors.Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
- Robertson, David W.,Lacefield, William B.,Bloomquist, William,Pfeifer, William,Simon, Richard L.,Cohen, Marlene L.
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p. 310 - 319
(2007/10/02)
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- Benzothiophenes and benzofurans and antiallergic use thereof
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Novel benzothiophene and benzofuran derivatives having antiallergic activity are described as well as a method of manufacture, pharmaceutical compositions, and methods of use therefor. The disclosure describes the use of derivatives for prevention of the release of mediators including histamine and leukotrienes from basophils and mast cells, and prevent respiratory burst in neutrophils providing activity useful in cardiovascular disorders as well as in antiinflammatory, psoriasis, and antimigraine treatment.
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