1,721,011 research outputs found
Nanomolar beta-lactamase inhibitors
No full textNew .alpha.-boronated N-alkylamides, R1C(O)NHCHR2B(OH)2 (R1 = H, organyl, excluding R1 = Me, Ph; R2 = heterocyclyl, cycloalkenyl, alkenyl, alkyl), preferably N-acyl-3-aminomethylbenzoates (.alpha.R)-RC(O)NHCH[B(OH)2]-1,3-C6H4X [15-17; X = CO2H, R = Me, 2-thienylmethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl; 21, X = H, R = 2-thienylmethyl], designed as transition-state analog inhibitors effective against class C .beta.-lactamase AmpC, were prepd. by one-pot procedure comprising stereoselective dichlorocarbene insertion into B-C-bond of (+)-pinanediol 3-(4,4-dimethyl-2-oxazolinyl)phenylboronate (7), amination of the resulting QO2BCHCl-1,3-C6H4R3 [8; Q = (+)-pinanediyl, R3 = 4,4-dimethyl-2-oxazolinyl] and subsequent acylation. The new compds. improve inhibition by over two-orders of magnitude compared to analogous glycylboronic acids, with Ki values as low as 1 nM. In an example, (+)-pinanediol (1R)-1-(2-thienylacetylamino)-1-[3-(4,4-dimethyl-4,5-dihydro-2-oxazolyl)phenyl]methylboronate (11) was prepd. from 7 by reaction with LiCHCl2 at -80, followed by amination by LiN(TMS)2, desilylation, and acylation by Ac2O with 24% overall yield. In another example, compd. 10 was deprotected to give 3-[(R)-(borono)(2-thienylacetylamino)methyl]benzoic acid (16). Compd. 16 exhibited binding const. with AmpC .beta.-lactamase of 0.001 .mu.M, and synergic inhibiting effect on E.coli growth at min. inhibition concn. (MIC) of 1.mu.g/mL in combination with antibiotic ceftazidime; in the absence of 16 the MIC of ceftazidime was 32 .mu.g/mL
Amide Boronic Acid Inhibitors of AmpC b-lactamase to Reverse Bacterial Resistance to b-lactam Antibiotics.
No full textThe invention provides novel non-g(b)-lactamases. In particular, the invention provides such inhibitors which are boronic acids of formula (1) which is set forth in the specification. These compounds may be used with g(b)-lactam-antibiotic-resistant bacterial infections. Finally, the invention provides a pharmaceutical composition comprising these compounds
Sulfonamide Boronic Acid Inhibitors of AmpC b-lactamase to Reverse Bacterial Resistance to b-lactam Antibiotics.
No full textThe invention provides novel non-g(b)-lactamases. In particular, the invention provides such inhibitors which are boronic acids of formula (1) which is set forth in the specification. These compounds may be used with g(b)-lactam-antibiotic-resistant bacterial infections. Finally, the invention provides a pharmaceutical composition comprising these compound
Progettazione, Sintesi ed Attività di Acidi 1-Acilamminoalcanboronici Inibitori di beta-Lattamasi
No full textStructure-based inhibitor design vs. beta-lactamase
No full textFragment-based screens test multiple low-molecular weight molecules for binding to a target. Fragments often bind with low affinities but typically have better ligand efficiencies (DeltaG(bind)/heavy atom count) than traditional screening hits. This efficiency, combined with accompanying atomic-resolution structures, has made fragments popular starting points for drug discovery programs. Fragment-based design adopts a constructive strategy: affinity is enhanced either by cycles of functional-group addition or by joining two independent fragments together. The final inhibitor is expected to adopt the same geometry as the original fragment hit. Here we consider whether the inverse, deconstructive logic also applies--can one always parse a higher-affinity inhibitor into fragments that recapitulate the binding geometry of the larger molecule? Cocrystal structures of fragments deconstructed from a known beta-lactamase inhibitor suggest that this is not always the case
Phenylboronic acid derivative inhibitors of ?-lactamases, their preparation, pharmaceutical compositions, and therapeutic use.
No full texthgkjh
3-Aminophenylboronic acid derivative inhibitors of β-lactamases, their preparation, and their therapeutic use
No full textNon-β-lactam inhibitors of β-lactamases are provided. In particular, the invention provides such inhibitors which are aminophenylboronic acid derivs. I [R1 = (un)substituted lower alkyl, (un)substituted (hetero)cyclic alkene; Z = bond, O, S, lower (hetero)alkyl], or a pharmaceutically acceptable salt thereof. These compds. may be used with β-lactam antibiotics to treat β-lactam-antibiotic-resistant bacterial infections. Finally, the invention provides a pharmaceutical compn. comprising these compds
Phenylboronic acid derivative inhibitors of β-lactamases, their preparation, pharmaceutical compositions, and therapeutic use
No full textNon-β-lactam inhibitors of β-lactamases are provided. In particular, the invention provides such inhibitors which are phenylboronic acids I [R1 = N-lower alkyl, (un)substituted (hetero)cyclic alkene] or a pharmaceutically acceptable salt thereof. These compds. may be used with β-lactam antibiotics to treat β-lactam-antibiotic-resistant bacterial infections. Finally, the invention provides a pharmaceutical compn. comprising these compds
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
- …
