- Design, synthesis, and evaluation of transition-state analogs as inhibitors of the bacterial quorum sensing autoinducer synthase CepI
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Quorum sensing is a bacterial signaling system that involves the synthesis, secretion and detection of signal molecules called autoinducers. The main autoinducer in Gram-negative bacteria are acylated homoserine lactones, produced by the LuxI family of autoinducer synthases and detected by the LuxR family of autoinducer receptors. Quorum sensing allows for changes in gene expression and bacterial behaviors in a coordinated, cell density dependent manner. Quorum sensing controls the expression of virulence factors in some human pathogens, making quorum sensing an antibacterial drug target. Here we describe the design and synthesis of transition-state analogs of the autoinducer synthase enzymatic reaction and the evaluation of these compounds as inhibitors of the synthase CepI. One such compound potently inhibits CepI and constitutes a new type of inhibitor against this underdeveloped antibacterial target.
- Higgins, Erin L.,Kellner-Rogers, Julian S.,Estanislau, Alexandra M.,Esposito, Alec C.,Vail, Nora R.,Payne, Sterling R.,Stockwell, Julia G.,Ulrich, Scott M.
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supporting information
(2021/03/15)
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- Identification and application of enantiocomplementary lactamases for Vince lactam derivatives
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Four enzymes showing hydrolytic activity on derivatives of 2-azabicyclo[2.2.1]hept-5-en-3-one (Vince lactam) were successfully identified through analysis of protein crystal structure and amino acid sequence alignments. Enantiocomplementary activities were observed on Vince lactam and its saturated analog 2-azabicyclo[2.2.1]heptan-3-one with non-heme chloroperoxidase (CPO-T) from Streptomyces aureofaciens, cyclic imide hydrolase (CIH) from Pseudomonas putida, polyamidase (NfpolyA) from Nocardia farcinica, and amidase (AMI) from Rhodococcus globerulus, and perfect kinetic resolution was achieved (E>200). Computational analysis of amide bond resonance stabilization in lactams correlated well with the overall reactivity pattern of the lactams as a function of ring size and strain. The biocatalysts cloned and investigated in this study could be of interest for the synthesis of enantiopure carbocyclic nucleoside analogues.
- Assaf, Zeinab,Eger, Elisabeth,Vitnik, Zeljko,Fabian, Walter M. F.,Ribitsch, Doris,Guebitz, Georg M.,Faber, Kurt,Hall, Mélanie
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p. 2517 - 2521
(2015/04/14)
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- ALKYLAMINO, ARYLAMINO, AND SULFONAMIDO CYCLOPENTYL AMIDE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of the formula (I) which are modulators of chemokine receptor activity useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
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Page/Page column 43
(2010/11/27)
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- AMINOCYCLOPENTYL PYRIDOPYRAZINONE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of Formula I and Formula II (wherein A, E, j, k, m, n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, R17, R18, R19, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, X, Y and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
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Page/Page column 30
(2010/11/27)
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- TETRAHYDROPYRANYL CYCLOPENTYL TETRAHY-DROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of Formula I (wherein n, R1, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, Y and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory
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Page/Page column 29-30
(2008/06/13)
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- 3,3-DISUBSTITUTED TETRAHYDROPYRANYL CYCLOPENTYL AMIDE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of Formula I (wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, R17, R18, Y and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and im
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Page/Page column 29
(2008/06/13)
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- Synthesis of optically active monothioimides with chirality due to sulphur substitution
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Two optically active bicyclic monothioimides were prepared via chiral derivatives of cis-1,2-cyclopropanedicarboxylic and cis-1,3-cyclopentanedicarboxylic acids and their absolute configurations were assigned.
- Milewska,Polonski
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p. 359 - 362
(2007/10/02)
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- Enantioselective synthesis of (+) and (-)-cis-3-aminocyclopentanecarboxylic acids by enzymatic asymmetrization
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Both enantiomers of cis-3-aminocyclopentanecarboxylic acid (GABA analogs, inhibitory neurotransmitter) have been prepared via enzymatic asymmetrization of cis -1,3-cyclopentanedicarboxylic acid.
- Chenevert,Martin
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p. 199 - 200
(2007/10/02)
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- Synthesis of Either Enantiomer of cis-3-Aminocyclopentanecarboxylic Acid from Both Enantiomers of Racemic 2-Azabicyclohept-5-en-3-one
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(-)-2-Azabicyclohept-5-en-3-one (-)-1 was converted into (-)-cis-3-aminocyclopentanecarboxylic acid (-)-2 in two steps and into the enantiomeric amino-acid (+)-2 in three steps.
- Evans, Chris,McCague, Ray,Roberts, Stanley M.,Sutherland, Alan G.
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p. 656 - 657
(2007/10/02)
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