- Discovery of novel β-lactam amalgamated 4-methylthiazole-5-carboxylic acid derivatives as potential antimicrobial agents
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Penicillin binding proteins are the essential component for the bacterial cell wall synthesis, which has been identified as potential targets for the development of new β-lactam containing antimicrobial agents. In view of this, a series of substituted 2-(2-chloro-3-oxo-4-phenylazetidin-1-yl)-4-methylthiazole-5-carboxylic acid derivatives (5a-r) were synthesized and characterized by FTIR, 1H-NMR, 13C-NMR and mass spectrometry. The synthesized β-lactam ring containing thiazole carboxylic acid derivatives (5a-r) were screened for antibacterial activity against E. coli NCTC 10418, S. aureus NCTC 65710, P. aeruginosa NCTC 10662, B. subtilis MTCC 1133 and S. typhi MTCC 1253. The outcomes of anti-bacterial screening showed that among all the screened compounds, five compounds viz. 5b, 5c, 5f, 5k, and 5o showed moderate to good anti-bacterial activity having MIC values between 3.25-25 μg/mL. Three compounds of the series that is, 5a, 5d and 5e showed most promising antibacterial activity against E. coli NCTC 10418, S. aureus NCTC 65710, P. aeruginosa NCTC 10662, B. subtilis MTCC 1133 and S. typhi MTCC 1253 having MIC value 6.25 μg/mL. In addition, these three potential molecules were also studied for possible binding on penicillin binding protein by molecular docking and for druggable characteristics ADMET studies (PDB ID: 2Z2M).
- Arshad, Mohammed Faiz,Al-Otaibi, Faisal,Kumar, Suresh,Nagarethinam, Sivagurunathan,Elkerdasy, Ahmed,Upmanyu, Neeraj
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p. 1699 - 1709
(2017/12/15)
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- Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4- methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases
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Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.
- Oka, Yusuke,Yabuuchi, Tetsuya,Oi, Takahiro,Kuroda, Shoichi,Fujii, Yasuyuki,Ohtake, Hidenori,Inoue, Tomoyuki,Wakahara, Shunichi,Kimura, Kayo,Fujita, Kiyoko,Endo, Mayumi,Taguchi, Kyoko,Sekiguchi, Yoshinori
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p. 7578 - 7583
(2014/01/06)
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- Discovery of the first inhibitors of bacterial enzyme D-aspartate ligase from Enterococcus faecium (Aslfm)
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The D-aspartate ligase of Enterococcus faecium (Aslfm) is an attractive target for the development of narrow-spectrum antibacterial agents that are active against multidrug-resistant E. faecium. Although there is currently little available information regarding the structural characteristics of Aslfm, we exploited the knowledge that this enzyme belongs to the ATP-grasp superfamily to target its ATP binding site. In the first design stage, we synthesized and screened a small library of known ATP-competitive inhibitors of ATP-grasp enzymes. A series of amino-oxazoles derived from bacterial biotin carboxylase inhibitors showed low micromolar activity. The most potent inhibitor compound 12, inhibits Aslfm with a Ki value of 2.9 μM. In the second design stage, a validated ligand-based pharmacophore modeling approach was used, taking the newly available inhibition data of an initial series of compounds into account. Experimental evaluation of the virtual screening hits identified two novel structural types of Aslfm inhibitors with 7-amino-9H-purine (18) and 7-amino-1H-pyrazolo[3,4-d]pyrimidine (30 and 34) scaffolds, and also with Ki values in the low micromolar range. Investigation the inhibitors modes of action confirmed that these compounds are competitive with respect to the ATP molecule. The binding of inhibitors to the target enzyme was also studied using isothermal titration calorimetry (ITC). Compounds 6, 12, 18, 30 and 34 represent the first inhibitors of Aslfm reported to date, and are an important step forward in combating infections due to E. faecium.
- ?kedelj, Veronika,Perdih, Andrej,Brvar, Matja?,Krofli?, Ana,Dubbée, Vincent,Savage, Victoria,O'Neill, Alex J.,Solmajer, Tom,Be?ter-Roga?, Marija,Blanot, Didier,Hugonnet, Jean-Emmanuel,Magnet, Sophie,Arthur, Michel,Mainardi, Jean-Luc,Stojan, Jure,Zega, Anamarija
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p. 208 - 220
(2013/10/01)
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- AMINOTHIAZOLE DERIVATIVE
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A compound represented by formula (1) or a pharmaceutically acceptable salt thereof, which has a PI3 kinase 3 inhibitory effect and is useful as a prophylactic or therapeutic agent for articular rheumatism, Crohn''s disease, irritable colitis, Sjoegren''s syndrome, multiple sclerosis, systemic lupus erythematosus, asthma, atopic dermatitis, arteriosclerosis, organ transplant rejection, cancer, retinopathy, psoriasis, arthrosis deformans, age-related macular degeneration, type II diabetes, insulin resistance, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hyperlipemia, etc.
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Page/Page column 8-9
(2012/09/10)
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- QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
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The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.
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Page/Page column 51
(2008/12/06)
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- HETEROCYCLIC ORGANIC COMPOUNDS
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The present application provides compounds of formula (I) that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.
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Page/Page column 46
(2008/06/13)
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- ORGANIC COMPOUNDS
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The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.
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Page/Page column 91-92; 100
(2008/12/08)
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- 2-SUBSTITUTED 5-MEMBERED HETEROCYCLES AS SCD INHIBITORS
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The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed
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Page/Page column 75
(2008/12/06)
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- AMINOTHIAZOLE DERIVATIVES AS HUMAN STEAROYL-COA DESATURASE INHIBITORS
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Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I), where V, W, R1, R2, R3 and R4 are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
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Page/Page column 47
(2008/06/13)
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- Design and Synthesis of Novel Thiazole-Containing Cross-Linked Polyamides Related to the Antiviral Antibiotic Distamycin
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A family of naturally occurring oligopeptides includes netropsin, distamycin, anthelvencin, kikumycin B, amidinomycin, and norformycin. Netropsin (I) and distamycin (II) express their biological activities by targeting specific sequences of chemical functionalities in the minor groove of DNA. Both netropsin and distamycin can be regarded as polyamide chains in which each α-carbon has been replaced by a five-membered pyrrole ring. The repeat distance in such an augmented polyamide chain is almost the same as the distance from one base pair to the next along the floor of a minor groove within β-DNA. In this paper we report the synthesis of 16-21 cross-linked polyamides containing a thiazole heterocyclic ring bearing the active functionalites NH2, NHCHO, or H. 16 and 17 were synthesized by DCC and HOBt catalyzed reaction of 5 with 14 and 15, while the formylation products 18 and 19 were obtained by coupling the formylated 4-methyl-thiazolated acid 6 with 14 and 15. The deaminated compounds 20 and 21 were obtained by the coupling of 5-trichloroacetyl-4-methylthiazole 7 synthesized from 4-methylthiazole. All the six cross-linked polyamides 16-21 were tested for their DNA gyrase inhibition. The studies have shown these polyamides have better sequence recognition and a greater percentage of inhibition than the corresponding monomers. The compound 17 shows complete inhibition of gyrase at 0.5 μM concentration as compared to the naturally occurring distamycin at 1.0 μM.
- Sharma, Sanjay K.,Tandon, Manju,Lown, J. William
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p. 1102 - 1107
(2007/10/03)
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