- New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens
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The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078–0.0625 μg/mL) and Gram-negative pathogens (MICs: range, 1–2 μg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.
- Durcik, Martina,Nyerges, ákos,Skok, ?iga,Skledar, Darja Gramec,Trontelj, Jurij,Zidar, Nace,Ila?, Janez,Zega, Anamarija,Cruz, Cristina D.,Tammela, P?ivi,Welin, Martin,Kimbung, Yengo R.,Focht, Dorota,Benek, Ond?ej,Révész, Tamás,Draskovits, Gábor,Szili, Petra éva,Daruka, Lejla,Pál, Csaba,Kikelj, Danijel,Ma?i?, Lucija Peterlin,Toma?i?, Tihomir
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- Analysis of new Piperidine substituted Benzothiazole crystalline Derivatives
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Recently, heterocyclic compounds play important role in drug industries. The benzothiazole (BTA) is a bicyclic compound in heterocyclic because of their biological properties. In this paper the synthesis and characterization of benzothiazole were reported
- Rajesh, R.,Senthilkumar, S.,Shafi, S. Syed,Subaash, R.
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p. 1158 - 1166
(2021/11/17)
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- NEW CLASS OF DNA GYRASE AND/OR TOPOISOMERASE IV INHIBITORS WITH ACTIVITY AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA
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The present invention relates to compounds having a structure of general formula (I), processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in humans and warm-blooded animals.
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Page/Page column 98
(2020/03/29)
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- HETEROCYCLIC COMPOUNDS AND USE THEREOF AS MODULATORS OF TYPE III RECEPTOR TYROSINE KINASES
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Provided herein are heterocyclic compounds for treatment of CSF1R, FLT3, KIT, and/or PDGFRβ kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Paragraph 0319
(2016/08/03)
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- SUBSTITUTED BENZOTHIAZOLE AND BENZOXAZOLE DERIVATIVES USEFUL AS INHIBITORS OF DPP-1
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The present invention is directed to substituted benzothiazole and benzoxazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by DPP-1.
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Page/Page column 21
(2011/07/06)
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- HETEROAROMATIC COMPOUNDS AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heteroaromatic compounds of structural formula (I) are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD). The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and met
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Page/Page column 42
(2010/04/27)
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- Benzothiazole based inhibitors of p38α MAP kinase
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Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38α MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by t
- Liu, Chunjian,Lin, James,Pitt, Sidney,Zhang, Rosemary F.,Sack, John S.,Kiefer, Susan E.,Kish, Kevin,Doweyko, Arthur M.,Zhang, Hongjian,Marathe, Punit H.,Trzaskos, James,Mckinnon, Murray,Dodd, John H.,Barrish, Joel C.,Schieven, Gary L.,Leftheris, Katerina
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p. 1874 - 1879
(2008/12/21)
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- FIBROSIS INHIBITOR
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Medicament being useful as a fibrosis inhibitor for organs or tissues, which comprises a compound of the formula (I): wherein Ring Z is optionally substituted pyrrole ring, etc.; W2 is -CO-, -SO2-, optionally substituted C1-C4 alkylene, etc.; Ar2 is optionally substituted aryl, etc.; W1 and Ar1 mean the following (1) and (2):(1) W1 is optionally substituted C1-C4 alkylene, etc.; Ar1 is optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms:(2) W1 is optionally substituted C2-C5 alkylene, optionally substituted C2-C5 alkenylene, etc.; and Ar1 is aryl or monocyclic heteroaryl, which is substituted by carboxyl, alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W1, or a pharmaceutically acceptable salt thereof.
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- FUSED HETEROCYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: wherein (a) X is selected from the group consisting of a single bond, O, S. S(O)2 and N; (b) U is an aliphatic linker; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; (d) E is C(R3) (R4)A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamidek, sulfonamide and acylsulfonamide; (e) B is selected from the group consisting of S, O, C, and N; (f) Z is selected from the group consisting of N and C; with the proviso that when B is C then Z is N.
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Page 148-149
(2008/06/13)
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- Pyrrole derivatives
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Pyrrole derivatives represented by the following formula: wherein Ring Z is an optionally substituted pyrrole ring, etc.; W2 is —CO—, —SO2—, an optionally substituted C1-C4 alkylene, etc.; Ar2 is an optionally substituted aryl, etc.; W2 and Ar1 mean the following (1) and (2): (1) W1 is an optionally substituted C1-C4 alkylene, etc.; Ar1 is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms: (2) W1 is an optionally substituted C2-C5 alkylene, an optionally substituted C2-C5 alkenylene, etc.; and Ar1 is an aryl or monocyclic heteroaryl, which are substituted by carboxyl, an alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W1, or a pharmaceutically acceptable salt thereof These compounds are useful as medicaments such as a fibrosis inhibitor for organs or tissues.
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- Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment
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Carbapenems of the formula: STR1 are disclosed as useful antibacterial agents. Pharmaceutical compositions and methods of use are also disclosed.
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- 3-thioheteroaryl cephalosporin compounds, compositions and methods of use
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Cephalosporin compounds of the formula I STR1 are disclosed. The compounds are useful against MRSA/MRCNS. Compositions and methods of use are also included.
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- 3-thioheteroaryl 1-carba-1-dethiacephalosporin compounds, compositions and methods of use
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1-Carba-1-dethiacephalosporin compounds of the formula I STR1 are disclosed. The compounds are useful against MRSA/MRCNS. Compositions and methods of use are also included.
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