- Design and Synthesis of 4-Alkylidene-β-lactams: Benzyl- and Phenethyl-carbamates as Key Fragments to Switch on Antibacterial Activity
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The emergence of multidrug-resistant bacterial strains is particularly important in chronic pathologies such as cystic fibrosis (CF), in which persistent colonization and selection of resistant strains is favored by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients that has an associated increased multidrug resistance. In previous studies we demonstrated that the presence of a 4-alkylidene side chain directly linked to a β-lactam appeared to strengthen the potency against S. aureus, especially against methicillin-resistant S. aureus (MRSA) strains. In the present study, 21 new 4-alkylidene-β-lactams were synthesized and evaluated for antibacterial activity. We designed the new compounds to have aryl, benzyl, or phenethyl-carbamate groups on the C3 hydroxyethyl side chain. We found a correlation between biological activity and the nitrogen substituent of the carbamate group, and two phenethyl-carbamate β-lactams were shown to be valuable antibacterial agents against selected linezolid-resistant strains, with a minimum inhibitory concentrations of 2–4 mg L?1.
- Giacomini, Daria,Martelli, Giulia,Piccichè, Miriam,Calaresu, Enrico,Cocuzza, Clementina Elvezia,Musumeci, Rosario
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Read Online
- Amide compound, pharmaceutical composition, preparation method and application thereof
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The invention provides an amide compound, a pharmaceutical composition, a preparation method and application thereof and belongs to the field of medicine. Structure of the amide compound is shown as aformula I. The preparation method includes: in an alkaline condition and in an organic solvent, allowing a compound I and a compound II to be in condensation reaction. The amide compound or pharmaceutically acceptable salt thereof have long-acting sensory and/or motion blocking activity, can be used for preparing long-acting local anesthetic or analgesic and is long in efficacy lasting time, little side effect and high in medication safety.
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Paragraph 0157-0160
(2018/09/11)
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- NOVEL CYCLICSULFONIMIDOYLPURINONE COMPOUNDS AND DERIVATIVES FOR THE TREATMENT AND PROPHYLAXIS OF VIRUS INFECTION
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The present invention relates to compounds of formula (I), wherein R1, R2 and R3 and n are as described herein, or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.
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Page/Page column 19; 29
(2018/05/24)
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- Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins
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A mild method to convert optically pure amino acid thiourea and urea derivatives to thiohydantoins and hydantoins, respectively, is described. It provides an efficient way to realize enantioselective synthesis of thiohydantoins and hydantoins with good to high isolated yields and enantiomeric purities. We found that the enantiomeric purities were highly dependent on the reaction conditions including bases, solvents, and temperature.
- Chen, Yu,Su, Li,Yang, Xinying,Pan, Wenyan,Fang, Hao
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p. 9234 - 9239
(2015/11/27)
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- Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors
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A number of 1,2-benzisothiazol-3-one derivatives were prepared through structural modification of the original compound from high-throughput screening. Some analogues (e.g., 6b, 6r, 6s and 6w) were identified as novel and potent caspase inhibitors with IC50 of nanomolar. Structure-activity relationship (SAR) studies for caspase-3 inhibition were evaluated in vitro. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The present small molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis.
- Liu, Dazhi,Tian, Zhen,Yan, Zhihui,Wu, Lixin,Ma, Yan,Wang, Quan,Liu, Wei,Zhou, Honggang,Yang, Cheng
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p. 2960 - 2967
(2013/07/28)
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- Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines
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Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC 50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4′, 5′-f][1,3]diazepine structural skeleton of the lead compound 1.
- Kondaskar, Atul,Kondaskar, Shilpi,Fishbein, James C.,Carter-Cooper, Brandon A.,Lapidus, Rena G.,Sadowska, Mariola,Edelman, Martin J.,Hosmane, Ramachandra S.
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p. 618 - 631
(2013/02/25)
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- Development of synthetic aminopeptidase N/CD13 inhibitors to overcome cancer metastasis and angiogenesis
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Cancer metastasis is a major barrier to its treatment and an important cause of patient death. Antimetastatic agents hold promise for patients with advanced metastatic tumors. Aminopeptidase N/CD13 (APN) is being pursued by many as an important target against cancer metastasis and angiogenesis, but there are few reports on the in vivo evaluation of synthetic APN inhibitors. Herein, a series of compounds targeting APN were synthesized and evaluated for their antimetastasis and antiangiogenesis potency both in vitro and in vivo. Excitingly, compounds 4m, 4t, and 4cc, with the most potent APN inhibitory activities, displayed significant antimetastasis and antiangiogenesis effects in vitro and in vivo, suggesting that those synthetic APN inhibitors have the potential to overcome cancer metastasis and angiogenesis.
- Su, Li,Cao, Jiangying,Jia, Yuping,Zhang, Xiaonan,Fang, Hao,Xu, Wenfang
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supporting information
p. 959 - 964
(2013/02/23)
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- Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: An fast and atom efficient access to 1-aryl-3-benzylureas
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The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC50 = 140 nM) and the pyridylurea 62 (IC 50 = 98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC50 = 330 nM) in our assays.
- Monte, Fabio Lo,Kramer, Thomas,Bol?nder, Alexander,Plotkin, Batya,Eldar-Finkelman, Hagit,Fuertes, Ana,Dominguez, Juan,Schmidt, Boris
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supporting information; experimental part
p. 5610 - 5615
(2011/10/09)
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- "TRPV1 VANILLOID RECEPTOR ANTAGONISTS WITH A BICYCLIC PORTION"
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The invention discloses compounds of formula I wherein Y is a group of formula A, B, C, D, or E: and W, Q, n, R1, R2, R3, U1-U5, J and K have the meanings given in the description. The compounds of formula I are TRPV1 antagonists and are useful as active
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Page/Page column 36; 37
(2011/10/13)
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- TRPV1 vanilloid receptor antagonists with a bicyclic portion
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The invention discloses compounds of formula I wherein Y s selected from a group of formula and W, Q, n, R1, R2, R3, U1-U5 have the meanings given in the description. The compounds of formula I are TRPV1 antagonists and are useful as active ingredients of pharmaceutical compositions for the treatment of pain and other conditions ameliorated by the inhibition of the vanilloid receptor TRPV1. 1.
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Page/Page column 14-15
(2011/11/01)
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- Discovery of N-benzyl-N′-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (I): Optimization of the amine portion
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Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.
- Duan, Maosheng,Peckham, Jennifer,Edelstein, Mark,Ferris, Robert,Kazmierski, Wieslaw M.,Spaltenstein, Andrew,Wheelan, Pat,Xiong, Zhiping
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scheme or table
p. 7397 - 7400
(2011/02/23)
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- Organosilicon synthesis of isocyanates: II. Synthesis of aliphatic, carbocyclic, and fatty-aromatic isocyanates
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Silylation of a series of aliphatic, carbocyclic, and fatty-aromatic amines gave the corresponding silyl derivatives whose yield depended on the electronic and steric structure of the substrate and the nature of the silylating agent. The yield of isocyanates obtained by phosgenation of the silyl derivatives under mild conditions decreased in going from aliphatic amines to benzylamines and rose as the length of the alkyl chain in fatty-aromatic amines extended. The most convenient procedure for the synthesis of low-boiling alkyl isocyanates was found to be based on the transformation of amines or ammonium salts into silyl or silyl silyl-carabamates, followed by pyrolysis of the latter in the presence of trichloro(phenyl)silane. Pleiades Publishing, Inc., 2006.
- Lebedev,Lebedeva,Sheludyakov,Ovcharuk,Kovaleva,Ustinova
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p. 469 - 477
(2008/02/07)
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- Azepinoindole derivatives as pharmaceutical agents
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Compounds, compositions and methods for modulating the activity of receptors are provided. In particular, compounds and compositions are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder directly or indirectly related to the activity of the receptors.
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- Efficient synthesis of 2,9-disubstituted 8-hydroxyadenine derivatives
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An efficient and general method for the synthesis of 2,9-disubstituted 8-hydroxyadenines, which are expected to have various biological activities, was realized. 5-amino-4-cyano-2-hydroxyimidazoles(1) were prepared from aminomalononitrile and isocyanates as key intermediates. The condensation of 1a with amidines, imidates, guanidine, urea and thioureas afforded 8-hydroxyadenines (2-6) possessing various substituents at the 2-position. Furthermore, selective alkylation of 2-amino- and 2-hydroxyadenines (4 and 6) successively proceeded to give the corresponding 2-alkylamino- and 2-alkoxyadenines (5 and 7), respectively. 2-Alkythioadenines (15) were prepared by an analogous reaction of 1a with benzoyl isothiocyanate and subsequent S-alkylation. The imidazoles 1 are most useful intermediated for the synthesis of 8-hydroxyadenine derivatives.
- Hirota, Kosaku,Kazaoka, Kazunori,Niimoto, Itaru,Sajiki, Hironao
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p. 1354 - 1365
(2007/10/03)
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- Supported 3,5-disubstituted chiral hydantoin: A practical catalyst for the asymmetric hydrocyanation of 3-phenoxybenzaldehyde
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A novel synthesis of six (R)-3,5-disubstituted chiral hydantoins in mixed solvent is reported. The catalysts were supported on a new polymeric resin afterwards and their enantioselectivities are examined via the asymmetric hydrocyanation of 3-phenoxybenzaldehyde.
- Zhai, Zhicai,Chen, Jinlong,Wang, Hailing,Zhang, Quanxing
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p. 1873 - 1883
(2007/10/03)
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- Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity
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The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4- yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log K(i) values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED50 values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
- Stark, Holger,Purand, Katja,Ligneau, Xavier,Rouleau, Agnès,Arrang, Jean-Michel,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
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p. 1157 - 1163
(2007/10/03)
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- Orally Active β-Lactam Inhibitors of Leukocyte Elastase-1. Activity of 3,3-Diethyl-2-azetidinones
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A thorough analysis of the mechanism of inhibition of human leukocyte elastase (HLE) by a monocyclic β-lactam and the mechanism of β-lactam hydrolysis led to the preparation of potent and highly stable inhibitors of HLE.This work led to the identification of 4--3,3-diethyl-1-carbonyl>-2-azetidinone (2) as the first orally active inhibitor of human leukocyte elastase (HLE).Analogs of 2 with different substituents on the urea N were synthesized and evaluated for their activity in vitro against HLE as well as in vivo in a hamster lung hemorrhage model.Compounds with a methyl or a methoxy group in the para position of the benzene ring were very potent in both assays.The results are discussed on the basis of the proposed model for the binding of this class of inhibitors to HLE and a possible mechanism of inhibition is presented.
- Shah, Shrenik K.,Dorn, Conrad P.,Finke, Paul E.,Hale, Jeffrey J.,Hagmann, William K.,et al.
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p. 3745 - 3754
(2007/10/02)
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