1,721,010 research outputs found
Boronic acid inhibitors of beta-lactamases as therapeutic agents in treatment of antibiotic-resistant infection diseases
No full texthe invention relates to novel boronic acid compounds, a method for the preparation of such compounds, intermediate compounds for the preparation of such compounds, intermediate compounds for the use in a method for preparation of such compounds, a pharmaceutical composition, the use of one or more compounds discussed above or of a pharmaceutical composition in the manufacture of a medicament for the treatment of a bacterial infection, and a screening method
Synthesis of [(1,2,3-Triazol-1-yl)methyl]boronic Acids Through Click Chemistry: Easy Access to a Potential Scaffold for Protease Inhibitors
No full textStereoselective synthesis of previously unreported [(1,2,3-triazol-1-yl)methyl]boronic acids has been achieved from azidomethylboronates by copper-catalyzed azide–alkyne cycloaddition reaction. The proximity of the cycloaddition reaction center to the boronic group is not detrimental to the stability of the sp3 C–B bond or to the stereoisomeric composition, which further expands the field of application of click chemistry to new boronate substrates and offers a new potential scaffold for protease inhibitors
Using Boronic Acid Transition State Inhibitors to understand the extended spectrum (ES) and carbapenemase phenotypes of class A beta-lactamases in Klebsiella pneumoniae
No full textA method of treating a bacterial infection in a subject in need thereof includes administering to the subject therapeutically effective amts. of at least one β-lactam antibiotic and at least one triazolylmethyl boronic acid β-lactamase inhibitor.
No full textA method of treating a bacterial infection in a subject in need thereof includes administering to the subject therapeutically effective amts. of at least one β-lactam antibiotic and at least one triazolylmethyl boronic acid β-lactamase inhibitor
Progettazione, Sintesi ed Attività di Acidi 1-Acilamminoalcanboronici Inibitori di beta-Lattamasi
No full textAcetamidomethaneboronic acids bearing the R1 side chains of beta-lactams as inhibitors of beta-lactamase enzymes
No full textThe invention provides a method of treating a .beta.-lactam-antibiotic-resistant bacterial infection with a combination of a .beta.-lactamanalog (acylaminomethaneboronic acid deriv.). The invention also provides a method of inhibiting a .beta.-lactamase comprising contacting the .beta.-lactamase with a .beta.-lactamanalog. Finally, the invention provides compds. which are .beta.-lactamanalogs and compns. contg. .beta.-lactam analogs
A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening
No full textHigh-throughput and virtual screening are widely used to discover novel leads for drug design.
On examination,many screening hits appear non-drug-like: they act noncompetitively,show
little relationship between structure and activity,and have poor selectivity. Attempts to develop
these peculiar molecules into viable leads are often futile,and much time can be wasted on
the characterization of these “phony” hits. Despite their common occurrence,the mechanism
of action of these promiscuous molecules remains unknown. To investigate this problem,45
diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of
various receptors,including â-lactamase,malarial protease,dihydrofolate reductase,HIV Tar
RNA,thymidylate synthase,kinesin,insulin receptor,tyrosine kinases,farnesyltransferase,gyrase,prions,triosephosphate isomerase,nitric oxide synthase,phosphoinositide 3-kinase,and integrase; 30 were from an in-house screening library of a major pharmaceutical company.
In addition to their original targets,35 of these 45 compounds were shown to inhibit several
unrelated model enzymes. These 35 screening hits included compounds,such as fullerenes,dyes,and quercetin,that have repeatedly shown activity against diverse targets. When tested
against the model enzymes,the compounds showed time-dependent but reversible inhibition
that was dramatically attenuated by albumin,guanidinium,or urea. Surprisingly,increasing
the concentration of the model enzymes 10-fold largely eliminated inhibition,despite a 1000-
fold excess of inhibitor; a well-behaved competitive inhibitor did not show this behavior. One
model to explain these observations was that the active form of the promiscuous inhibitors
was an aggregate of many individual molecules. To test this hypothesis,light scattering and
electron microscopy experiments were performed. The nonspecific inhibitors were observed to
form particles of 30-400 nm diameter by both techniques. In control experiments,a wellbehaved
competitive inhibitor and an inactive dye-like molecule were not observed to form
aggregates. Consistent with the hypothesis that the aggregates are the inhibitory species,the
particle size and IC50 values of the promiscuous inhibitors varied monotonically with ionic
strength; a competitive inhibitor was unaffected by changes in ionic strength. Unexpectedly,aggregate formation appears to explain the activity of many nonspecific inhibitors and may
account for the activity of many promiscuous screening hits. Molecules acting via this
mechanism may be widespread in drug discovery screening databases. Recognition of these
compounds may improve screening results in many areas of pharmaceutical interest
Acido alfa-Acetammido-alfa-Fenilmetanboronico come Agente Derivatizzante Chirale per la Determinazione dell’Eccesso Enantiomerico di 1,2-Dioli
No full textBiocatalytic asymmetric synthesis of (S)- and (R)-Timolol
No full textA new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro-1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure
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